JP2002167397A - Peptide derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel peptide derivative recognized as a ligand by a G protein conjugating recepter. SOLUTION: The peptide of this peptide derivative is expressed by the formula (1): P1-Arg-Pro-Arg-Leu-Phe-P2-P3-Gly-Pro-P4-P5, and can be used as (1) the development of a receptor bonding assay system using an expression system of a recombined receptor protein and the screening of medicine candidate compounds; (2) the development of medicine products, such as a regulator for the function of a nerve, circulation, heart, immune, digestive organ, metabolism, generative organ, or the like.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel peptide having a ligand activity for APJ which is an orphan G protein-coupled receptor protein, its use, and the like.

[0002]

2. Description of the Related Art Many hormones and neurotransmitters regulate biological functions through specific receptors present on cell membranes. Many of these receptors are conjugated
It performs intracellular signal transduction through the activation of guanine nucleotide-binding protein (hereinafter sometimes abbreviated as G protein), and has a common structure with seven transmembrane domains. These are collectively called receptors or seven-transmembrane receptors. Maintaining homeostasis in the living body, reproduction, individual development, metabolism, growth, nervous system, circulatory system, immune system, digestive system, metabolism through interaction of such hormones and neurotransmitters with G protein-coupled receptors Functions that are important to living organisms, such as system regulation, are being regulated. As described above, it is known that receptor proteins for various hormones and neurotransmitters exist in the regulation of biological functions and play an important role in regulating their functions, but unknown agents (hormones and neurotransmitters) are known. Etc.) and whether receptors for it are present are often still unknown. In recent years, utilizing the fact that G protein-coupled receptor proteins show similarity in amino acid sequence to a part of their structure,
Polymerase chain reaction
ain Reaction (hereinafter abbreviated as PCR)) to search for a DNA encoding a novel receptor protein. (Libert, F., et al. Science, 2
44, 569-572, 1989, Welch, SK, etal., Biochem. Bi
ophys. Res. Commun., 209, 606-613, 1995, Marchese,
A., et al., Genomics, 23, 609-618, 1994, Marchese,
A., Genomics, 29, 335-344, 1995). Genome D
New G protein-coupled receptor proteins have also been found one after another by random sequencing of NA or cDNA (Nomura, N., et al., DNA Research 1, 27.
-35, 1994). The only general means for determining the ligands of these orphan G protein-coupled receptor proteins has been to infer from the similarity in the primary structure of G protein-coupled receptor proteins. However, many orphan G protein-coupled receptor proteins often have low homology to a known receptor. In fact, unless the receptor is a receptor subtype of a known ligand, its ligand is identified only by its primary structural similarity. It was difficult to estimate. On the other hand, it has been estimated from genetic analysis that many orphan G protein-coupled receptors are still present because many orphan G protein-coupled receptors have been found. Few examples have identified ligands for receptors.
Recently, there has been reported an example in which a cDNA encoding an orphan G protein-coupled receptor protein was introduced into animal cells to search for a novel opioid peptide (Reinsheid,
RK et al., Science, 270, 792-794, 1995,
Menular, J.-C., et al., Nature 377, 532-535, 1
995). However, in this case, it was expected that the ligand easily belongs to the family of opioid peptides due to similarity and tissue distribution with known G protein-coupled receptor proteins. The history of research and development of substances acting on living organisms via opioid receptors has been long, and various antagonists / agonists have been developed. Therefore, an agonist for this receptor was found from a group of artificially synthesized compounds, and after using this as a probe to verify the expression of the receptor in receptor cDNA-transfected cells, the activity of an intracellular signaling system similar to that of the agonist was observed. And purifying it, and determining the structure of the ligand.

[0003] Further, a cDNA encoding a snail orphan G protein-coupled receptor (GRL104) is introduced into CHO cells, and a novel physiologically active peptide is expressed by using a specific increase in intracellular free calcium concentration in a receptor-expressing cell as an index. An identified example has been reported (Cox, K.
JA, et al., J. Neurosci., 17 (4), 1197-1205, 199
7) This novel bioactive peptide has high homology with known leucokinin, and GRL104 also has reactivity with known leucokinin. As described above, there are few orphan G protein-coupled receptor proteins whose ligands can be roughly estimated, especially when there is low similarity with the known G protein-coupled receptor protein family, there is little information on ligands, It was difficult to estimate the ligand. One of the reported orphan G protein-coupled receptors is APJ (O'D
owd, BF, et al., Gene, 436, 355-359, 1993). AP
J has low homology with the angiotensin receptor (AT1). The natural ligand for APJ and its partial peptides are available from Biochemical and Biophysical Reae
archCommunications 251, 471-476 (1998), WO 99
No./33976 (Japanese Patent Application No. 10-220853) and the like, but a modified product obtained by artificially modifying a natural ligand (for example, one or several constituent amino acids of a natural ligand are substituted with one or more constituent amino acids) Nothing is known about the substitution with another amino acid or the substitution of a side chain of one or several constituent amino acids of a natural ligand with an appropriate substituent.

[0004]

The natural ligand for APJ, an orphan G protein-coupled receptor expressed in the central nervous system, circulatory system, reproductive system, immune system, digestive system, etc., is artificially used. Modified peptides are considered to be more useful as pharmaceuticals and the like than natural ligands.
The structure and function of peptides more useful as drugs and the like have not been clarified.

[0005]

Means for Solving the Problems Based on this problem, the present inventors have developed various novel peptides by using, as an index, a change in the binding property between a peptide which is a modified form of the natural ligand and the above-mentioned receptor protein. By synthesizing and predicting and specifying the active site of the natural ligand, a modified form of the natural ligand that is more useful as a medicine was found.

That is, the present invention relates to a compound represented by the following formula (1): P1-Arg-Pro-Arg-Leu-Phe-P2-P3-Gly-Pro-P4-P5 (I) Or an amino acid residue or peptide chain consisting of 1 to 25 amino acids which may have different side chains,
2 represents a neutral amino acid residue whose side chain may be substituted or a basic amino acid residue whose side chain may be substituted, and P3 represents a neutral amino acid residue whose side chain may be substituted. Represents an aromatic amino acid residue whose side chain may be substituted or a basic amino acid residue whose side chain may be substituted, and P4 represents a neutral bond or a bond whose side chain may be substituted or An aromatic amino acid residue, wherein P5 is an amino acid residue whose side chain may be substituted or an amino acid derivative having its C-terminal carboxyl group reduced to a hydroxymethyl group or formyl group, a hydroxyl group or a side chain substituted A dipeptide chain formed by combining an amino acid residue which may be substituted with an amino acid residue whose side chain may be substituted or its C-terminal carboxyl group is reduced to a hydroxymethyl group or formyl group. Shows the peptide derivative, the side chain of -Arg-Pro-Arg-Leu-Phe- or -Gly-Pro- each amino acid residue in the middle in the formula may be substituted. (2) the peptide according to the above (1), wherein P1 is a hydrogen atom, pGlu or Arg-Arg-Gln, or its ester or its amide or a salt thereof; (3) The peptide according to the above (1), wherein P2 is His which may be substituted or Ala which may be substituted, or an ester thereof, an amide thereof or a salt thereof, and (4) P3 may be substituted. Arg or Lys which may be substituted
(5) -P4-P5, the peptide according to the above (1), an ester thereof, an amide thereof, or a salt thereof.
Is -Cha-Pro-Phe (Cl), -Cha-Pr
o-Phe, -Met-Pro-Phe, -Met-P
ro-Phe (Cl), -Cha-Phe or -Me
(6) The peptide according to the above (1), which is t-Phe, an ester thereof, an amide thereof, or a salt thereof.
Arg-Pro-Arg-Leu-Phe-Ala-Arg-Gly-Pro-Cha-Pro-Phe (C
l), Arg-Pro-Arg-Leu-Phe-His-Lys-Gly-Pro-Cha-Pro
-Phe (Cl), Arg-Pro-Arg-Leu-Phe-His-Lys-Gly-Pro-C
ha-Pro-Phe, Arg-Pro-Arg-Leu-Phe-His-Lys-Gly-Pro
-Met-Pro-Phe (Cl), Arg-Pro-Arg-Leu-Phe-Ala-Arg-G
ly-Pro-Met-Pro-Phe, Arg-Pro-Arg-Leu-Phe-His-Lys
-Gly-Pro-Cha-Phe (Cl), pGlu-Arg-Pro-Arg-Leu-Phe-
Arg-Arg-Gly-Pro-Met-Pro-Phe, pGlu-Arg-Pro-Arg-L
eu-Phe-His-Lys-Gly-Pro-Met-Pro-Phe or Arg-Pro
The peptide according to the above (1) represented by -Arg-Leu-Phe-Ala-Arg-Gly-Pro-Met-Phe, its ester or its amide or its salt, (7) the formula Q1-Arg-Pro-Arg -Leu-Ser-Ala-Q2-Gly-Q5 -Q3-Q4 (II) wherein Q1 is a hydrogen atom or 1 to 25 amino acids which may be the same or different and whose side chains may be substituted. Q represents an amino acid residue or a peptide chain;
2 represents a neutral amino acid residue whose side chain may be substituted, an aromatic amino acid residue whose side chain may be substituted or a basic amino acid residue whose side chain may be substituted,
Q3 represents a bond or a neutral or aromatic amino acid residue whose side chain may be substituted; Q4 represents an amino acid residue whose side chain may be substituted or its C-terminal carboxyl group is a hydroxymethyl group or An amino acid derivative reduced to a formyl group, a dipeptide chain in which an amino acid residue in which a hydroxyl group or a side chain may be substituted and an amino acid residue in which a side chain may be substituted or a C-terminal carboxyl group thereof is Represents a peptide derivative reduced to a hydroxymethyl group or a formyl group, Q5 represents a neutral amino acid residue whose side chain may be substituted, and -Arg-Pro-Arg-Leu-Ser-Ala in the formula
The side chain of each amino acid residue in-may be substituted. And (8) Q1 represents a hydrogen atom, p
(7) which is Glu or Arg-Arg-Gln
(9) A peptide in which Q2 may be substituted,
rg or the optionally substituted Lys, the peptide according to the above (7), an ester thereof, an amide thereof, or a salt thereof, and (10) -Q3-Q4 is -O
H, -Met, -Met-Pro-Phe, -Met-
Pro-Phe (Cl), -Cha-Pro-Phe,
-Cha-Pro-Phe (Cl), -Ala-Pro
-Phe (Cl), -Cha-Phe (Cl) or-
(11) Q5: the peptide according to the above (7), which is Cha, an ester thereof, an amide thereof, or a salt thereof;
Is the optionally substituted Pro, the optionally substituted Gly or the optionally substituted Ala, the peptide according to the above (7), an ester thereof, an amide thereof, or a salt thereof;

(12) (i) Arg-Arg-Gln-Arg-Pro-Arg-Le
u-Ser-Ala-Arg-Gly-Pro-Met-Pro-Phe (Cl), (ii) Arg-Pr
o-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Met-Pro-Phe (Cl), (ii
i) Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Cha-Phe (C
l), (iv) Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Cha-P
ro-Phe (Cl), (v) Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-Al
a-Arg-Gly-Pro-Cha, (vi) Arg-Pro-Arg-Leu-Ser-Ala-Ar
g-Gly-Pro-Cha-Pro-Phe, (vii) Arg-Arg-Gln-Arg-Pro-A
rg-Leu-Ser-Ala-Arg-Gly-Pro-Met-Pro-Phe, (viii) Arg
-Arg-Gln-Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Met,
(ix) Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-P
ro, (x) Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Met-Pr
o-Phe, (xi) pGlu-Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-P
ro-Met-Pro-Phe, (xii) Arg-Pro-Arg-Leu-Ser-Ala-Arg-
Gly-Pro-Met, (xiii) pGlu-Arg-Pro-Arg-Leu-Ser-Ala-L
ys-Gly-Pro-Met-Pro-Phe, (xiv) Arg-Pro-Arg-Leu-Ser-
Ala-Arg-Gly-Pro-Ala-Pro-Phe (Cl), (xv) Arg-Pro-Arg-
Leu-Ser-Ala-Arg-Gly-Gly-Met-Pro-Phe (Cl), (xvi) Arg
-Pro-Arg-Leu-Ser-Ala-Arg-Gly-NMe-Ala-Met-Pro-Phe (C
l), (xvii) Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Cha
-Pyn, (xviii) Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-
Cha-Pro-Pyn, (xix) Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser
-Ala-Arg-Gly-Gly-Cha, or (xx) Arg-Pro-Arg-Leu-S
er-Ala-Lys (Me) ₂ -Gly-Pro-Met-Pro-Phe, the peptide according to the above (7) or an ester or amide or a salt thereof, (13) a compound represented by the formula R1-Arg-Pro -Arg-Leu-Ser-His-Lys-Gly-Pro-R2-Pro-R3 (III) [wherein R1 is a hydrogen atom or 1 to 25, each of which may be the same or different and whose side chains may be substituted. An amino acid residue or peptide chain consisting of
2 represents an optionally substituted Cha, an optionally substituted Met or an optionally substituted Nle;
3 is an optionally substituted Phe (Cl), an optionally substituted Phe, an optionally substituted Nal
(2) represents optionally substituted Cha or optionally substituted Tyr, and represents -Arg-Pro-A in the formula.
rg-Leu-Ser-His-Lys-Gly-Pr
The side chain of each amino acid residue in o or -Pro- may be substituted. A peptide represented by the formula: or an ester or an amide or a salt thereof, (14) R1
Is a hydrogen atom, pGlu or Arg-Arg-Gln, a peptide thereof, an ester thereof, an amide thereof or a salt thereof, (15) Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-His -Lys-Gly-Pro
-Cha-Pro-Phe (Cl), Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Cha-Pro-Phe
(Cl), Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe
(Cl), pGlu-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Cha-Pr
o-Phe, pGlu-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pr
o-Phe (Cl), Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro
-Nle-Pro-Tyr, Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Nal
(2), pGlu-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pr
o-Nal (2), or Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Ch
a, the peptide according to the above (13) or an ester or an amide thereof or a salt thereof represented by the following formula: (16) (i)
Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Me
t (O), (ii) Arg-Arg-Lys (Arg-Arg) -Arg-Pro-Arg-Leu-Se
r-His-Lys-Gly-Pro-Met-Pro-Phe, (iii) Arg-Arg-Arg-A
rg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe, (i
v) Arg-Arg-Lys-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro
-Met-Pro-Phe, (v) Arg-Arg-Ala-Arg-Pro-Arg-Leu-Ser-
His-Lys-Gly-Pro-Met-Pro-Phe, (vi) Arg-Pro-Arg-Leu-
Ser-His-Lys-Gly-Pro-Met-Phe (Cl), (vii) pGlu-Arg-Pr
o-Arg-Leu-Ser-Arg-Lys-Gly-Pro-Met-Pro-Phe, (viii)
Arg-Arg-Phe-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Me
t-Pro-Phe, (ix) pGlu-Arg-Pro-Arg-Leu-Ser-His-Arg-G
ly-Pro-Met-Pro-Phe, (x) pGlu-Arg-Pro-Arg-Leu-Ser-H
is-Lys-Gly-Pro-Met-Phe (Cl), (xi) Arg-Pro-Arg-Leu-S
er-His-Lys-Gly-Pro-Met-Cha, (xii) pGlu-Arg-Pro-Arg
-Leu-Ser-Leu-Lys-Gly-Pro-Met-Pro-Phe, (xiii) Arg-P
ro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Nal (2), (xiv) p
Glu-Arg-Pro-Arg-Leu-Ser-Arg-Arg-Gly-Pro-Met-Pro-Ph
e, (xv) pGlu-Arg-Pro-Arg-Leu-Ser-Phe-Lys-Gly-Pro-M
et-Pro-Phe, (xvi) pGlu-Arg-Pro-Arg-Leu-Ser-His-Lys
-Gly-Pro-Met-Cha, (xvii) pGlu-Arg-Pro-Arg-Leu-Ser-
His-Lys-Gly-Pro-Met-Nal (2), (xviii) pGlu-Arg-Pro-A
rg-Leu-Ser-His-Phe-Gly-Pro-Met-Pro-Phe, (xix) pGlu
-Arg-Pro-Arg-Leu-Ser-His-Leu-Gly-Pro-Met-Pro-Phe,
(xx) Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-N
Me2, (xxi) Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-Ala-Arg
-Gly-Mor, (xxii) Arg-Pro-Arg-Leu-Ser-His-Ala-Gly-P
ro-Cha-Pro-Phe (Cl), (xxiii) Arg-Pro-Arg-Ala-Ser-Hi
s-Lys-Gly-Pro-Cha-Pro-Phe (Cl), (xxiv) Arg-Pro-Lys
(Me) ₂ -Leu-Ser-Ala-Arg-Gly-Pro-Met-Pro-Phe, (xxv) A
rg-Pro-Arg-Leu-Ser-Dap-Arg-Gly-Pro-Cha-Pro-Phe (C
l), (xxvi) Arg-Pro-Arg-Leu-Ser-Dap (Ac) c-Arg-Gly-Pr
o-Cha-Pro-Phe (Cl), (xxvii) Arg-Pro-Arg-Leu-Ser-Dap
(C6) -Arg-Gly-Pro-Cha-Pro-Phe (Cl), (xxviii) Arg-Pro
-Arg-Leu-Ser-Dap (Adi) -Arg-Gly-Pro-Cha-Pro-Phe (C
l) or (xxix) Arg-Pro-Ala-Leu-Ser-His-Lys-Gly-P
ro-Cha-Pro-Phe (Cl), a peptide thereof, an ester thereof, an amide thereof, or a salt thereof, (17) the above (1), (7), (13) or (1)
6) a medicament comprising the peptide or its ester or its amide or its salt according to 6), (18) a central nervous function regulator, a circulatory function regulator, a heart function regulator, an immune function regulator, a gastrointestinal function regulator. A medicament according to the above (17), which is a metabolic function regulator or a genital function regulator;
(19) The medicament according to the above (17), which is a preventive / therapeutic agent for HIV infection or AIDS, and (20) the above agent which is an agent of a protein containing the amino acid sequence represented by SEQ ID NO: 19 or a salt thereof. 17) The medicament according to the above, (21) the above (1), the above (7), the above (13) or the above (16)
(1), (7), (13) or (1) for the manufacture of a medicament comprising the peptide or its ester or its amide or its salt according to the above (1).
6) Use of the peptide or its ester or its amide or its salt according to (6), and (22) the above (1), (7), (13) or (16)
It is intended to provide a method for preventing or treating HIV infection or AIDS, which comprises administering the above-mentioned peptide or its ester, its amide or its salt to a mammal. Further, the present invention relates to (23) dementia, depression, hyperactivity child (microbrain disorder) syndrome, consciousness disorder, anxiety disorder, schizophrenia, phobia, growth hormone secretion disorder, bulimia, bulimia, high cholesterol Hyperglyceridemia, hyperlipidemia, hyperprolactinemia, diabetes, cancer, pancreatitis, renal disease, Turner syndrome, neurosis, rheumatoid arthritis, spinal cord injury, transient ischemic attack, muscle atrophy Treatment and prevention of diseases such as lateral sclerosis, acute myocardial infarction, spinocerebellar degeneration, fractures, wounds, atopic dermatitis, osteoporosis, asthma, epilepsy, infertility, arteriosclerosis, emphysema, pulmonary edema, lactation deficiency And a medicament according to the above (17).

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, amino acid residues
The amino acid loses a water molecule to form a peptide bond,
N-terminal when incorporated into proteins and peptides
Or the structure other than the C-terminal. For example, α-amino
An acid residue is an α-amino acid (H_TwoNC (R⁰) (R¹) COOH: R⁰and
R¹Each represents the same or different and represents an optional substituent
Loses water molecules to form peptide bonds,
N-terminus or C-terminus when incorporated into quality or peptide
-NHC (R⁰) (R¹) Refers to the structure of CO-. On the other hand, N
The terminal amino acid residue is H_TwoNC (R⁰) (R¹) CO-, C-terminal amino
The acid residue is -NHC (R⁰) (R¹) Indicated by COOH. Also, β-A
Amino acid (H_TwoNC (R⁰) (R¹) C (R^Two) (R^Three) COOH: R⁰, R¹, R^TwoYou
And R^ThreeAre the same or different and each has an optional substituent
Shown) loses water molecules to form peptide bonds and proteins
N-terminus or C-terminus when incorporated into quality or peptide
-NHC (R⁰) (R¹) C (R^Two) (R^Three) Refers to the structure of CO-.
On the other hand, the N-terminal amino acid residue is H_TwoNC (R⁰) (R¹) C (R^Two) (R^Three) C
O-, C-terminal amino acid residue is -NHC (R⁰) (R ¹) C (R^Two) (R^Three) COO
Indicated by H. Also, γ-amino acids (H_TwoNC (R⁰) (R¹) C (R^Two)
(R^Three) C (R^Four) (R^Five) COOH: R⁰, R¹, R^Two, R^Three, R^FourAnd R^FiveIs
The same or different, each represents an optional substituent)
Loss of water molecules to form peptide bonds, proteins and pep
Other than N-terminal or C-terminal when incorporated into the tide
Min-NHC (R⁰) (R¹) C (R^Two) (R^Three) C (R^Four) (R^Five) CO- structure
U. On the other hand, the N-terminal amino acid residue is H_TwoNC (R⁰) (R¹) C (R^Two)
(R^Three) C (R^Four) (R^Five) CO-, C-terminal amino acid residue is -NHC (R⁰) (R
¹) C (R^Two) (R^Three) C (R^Four) (R^Five) Indicated by COOH. Furthermore, ε-A
Amino acid (H_TwoNC (R⁰) (R¹) C (R^Two) (R^Three) C (R^Four) (R^Five) C (R⁶) (R⁷) C
(R⁸) (R⁹) COOH: R⁰, R¹, R^Two, R^Three, R^Four, R^Five, R⁶, R⁷, R⁸
And R⁹Are the same or different and each has an optional substituent
Loses water molecules to form peptide bonds and
N-terminal or C when incorporated into proteins or peptides
-NHC (R⁰) (R¹) C (R^Two) (R^Three) C (R^Four) (R^Five) C (R⁶)
(R⁷) C (R⁸) (R⁹) Refers to the structure of CO-. On the other hand, N-terminal amino
The acid residue is H_TwoNC (R⁰) (R¹) C (R^Two) (R^Three) C (R^Four) (R^Five) C (R⁶) (R⁷) C
(R⁸) (R⁹) CO-, C-terminal amino acid residue is -NHC (R⁰) (R¹) C (R
^Two) (R^Three) C (R^Four) (R^Five) C (R⁶) (R⁷) C (R⁸) (R⁹) Indicated by COOH.
As used herein, amino acids include natural and non-natural amino acids.
Natural amino acids, either in D-form or L-form
And any of α-, β-, γ-, and ε-type
Good. α-amino acid, β-amino acid, γ-amino acid, ε
The group forming the side chain of the amino acid includes (1) C
_1-6Alkyl group (eg, methyl, ethyl, n-propyl,
Isopropyl, n-butyl, isobutyl, sec-butyl
Tert-butyl, n-pentyl and the like, preferably
C_1-3Alkyl, etc.), (2) cyano group, (3) halogen
(Eg, fluorine, chlorine, bromine, iodine, etc.), (4) hydro
Kishi-C_1-6Alkyl group (eg, hydroxymethyl, hydrid
Roxyethyl, etc.), (5) C_1-6Alkoxy groups (eg, meth
Xy, ethoxy, n-propoxy, isopropoxy, n
-Butoxy, tert-butoxy and the like, preferably C
_1-3Alkoxy, etc.), (6) C_1-6Alkoxy-carboni
(E.g., methoxycarbonyl, ethoxycarbonyl,
Isopropoxycarbonyl, tert-butoxycarbo
Such as nyl, preferably C_1-3Alkoxy-carbonyl
Etc.), (7) C_1-4Acyl groups (eg, formyl, acetyl,
Formyl such as Lopionyl, Butyryl and C_2-4Al
(8) hydroxy group, (9) formula: -S (O) a
-R^{twenty one}(Where a is an integer of 0 to 2, R^{twenty one}Is C_1-6Al
Indicates a kill (specific examples include the same as above)
(For example, methylthio, methanesulfur
Nil, methanesulfonyl, ethylthio, ethanesulfi
Nil, ethanesulfonyl, etc.), (10) benzyloxyca
Rubonyl, (11) tosyl group, (12) carbamoyl group, (13)
Rucapto group, (14) amino group, (15) sulfo group, (16) phospho
Group, (17) phospho group, (18) carboxyl group, (19)
Tolazolyl group, (20) amino-C_1-6Alkyl group (eg,
Minomethyl, aminoethyl, etc.), (21) aminoallyl
Group, (22) thiazolyl group, (23) thienyl group, (24) oxazo
Ryl group, (25) furyl group, (26) pyranyl group, (27) pyridyl
Group, (28) pyrazyl group, (29) pyrazinyl group, (30) pyrimidi
Nyl group, (31) pyridazinyl group, (32) indolyl group, (33)
Indolinyl group, (34) isoindolyl group, (35) pyrrolyl
Group, (36) imidazolyl group, (37) isothiazolyl group, (3
8) pyrazolyl group, (39) chromenyl group, (40) purinyl group,
(41) quinolizinyl group, (42) quinolyl group, (43) isoquinolinyl group
Group, (44) quinazolinyl group, (45) quinoxalinyl group, (4
6) cinnolinyl group, (47) morpholinyl group, (48) benzothi
Enyl group, (49) benzofuranyl group, (50) benzimida
Soryl, (51) benzimidazolyl group, (52) C_3-8Cyclo
Alkyl group, (53) above (2), (3), (5) to (17), (20)
To C-substituted by the substituents described in (52)_1-4Alkyl
Group, (54) from (2), (3), (5) to (17), (20) to (52)
Formyl substituted with the substituents described above, C_2-4Arcanoy
C such as_1-4Acyl group, (55) the description of the above (1) to (52)
C such as phenyl substituted with a substituent_6-10Aryl group
(Mesityl, tolyl, xylyl, styrenyl, etc.), (5
6) Benzyl substituted with the substituents described in (1) to (52) above
C such as_7-15Aralkyl groups (methylbenzyl, methoxy,
Sibenzyl etc.), (57) C_7-15Aralkyl group (benzy
, Phenethyl, benzhydryl, naphthylmethyl
Etc.), (58) C_6-10Aryl groups (phenyl, naphthyl, i
And (59) a hydrogen atom.
You. In addition, the nitrogen atom is linked to the side chain forming the amino acid residue.
May form a ring (eg, proline, etc.)
May be combined to form a ring (eg, 3-amino
Rubornanecarboxylic acid, etc.).

Examples of α-amino acids include, for example, glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, lysine, arginine, phenylalanine, tyrosine, histidine, tryptophan, asparagine, Glutamine, proline, pipecolic acid, norleucine, γ-methylleucine, tert-leucine, norvaline, homoarginine, homoserine, α-aminoisobutyric acid, α-aminobutyric acid, ornithine, α-aminoadipic acid, phenylglycine, thienylglycine, cyclohexyl Glycine, cyclohexylalanine, thienylalanine, naphthylalanine, biphenylalanine, p
-Phosphonomethylphenylalanine, octahydroindole-2-carboxylic acid, O-phosphotyrosine, adamantylalanine, benzothienylalanine, pyridylalanine, piperidylalanine, pyrazylalanine, quinolylalanine, thiazolylalanine, homocysteine, homophenylalanine , Citrulline, homocitrulline, oxyproline (hydroxyproline), α, β-
Diaminopropionic acid, α, γ-diaminobutyric acid, aminomalonic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, cycloleucine, 2-amino-4-
Pentenoic acid and the like. Examples of β-amino acids include, for example, β-alanine, β-aminobutyric acid, isoasparagine, 3-aminoadipic acid, 3-aminophenylpropionic acid, 3-amino-2-hydroxy-4-phenylbutyric acid,
Examples include aminonorbornanecarboxylic acid and 3-aminobicycloheptanecarboxylic acid. Examples of γ-amino acids include, for example, γ-aminobutyric acid, isoglutamine, statin, 4-amino-3-hydroxy-5-cyclohexylpentanoic acid, 4-amino-3-hydroxy-5-phenylpentanoic acid, 6- Aminopenicillanic acid, 3-aminoadamantane-1-
And carboxylic acids. Examples of ε-amino acids include, for example, ε-aminocaproic acid, 4-aminomethyl-cyclohexanecarboxylic acid and the like. The natural amino acids include glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine,
Examples include cystine, methionine, aspartic acid, glutamic acid, lysine, arginine, phenylalanine, tyrosine, histidine, tryptophan, asparagine, glutamine, proline, ornithine, and citrulline. Non-natural amino acids include norleucine, γ
-Methylleucine, tert-leucine, norvaline, homoarginine, homoserine, aminoisobutyric acid, aminoadipic acid (eg, α-aminoadipic acid), phenylglycine, thienylglycine, cyclohexylglycine, aminobutyric acid, β-alanine, cyclohexylalanine, Thienylalanine, naphthylalanine, adamantylalanine, benzothienylalanine, pyridylalanine, piperidylalanine, pyrazylalanine, quinolylalanine, thiazolylalanine, isoasparagine, isoglutamine, homocysteine, homophenylalanine, homocitrulline, oxyproline ( Hydroxyproline),
Examples include diaminopropionic acid, diaminobutyric acid, aminobenzoic acid, N-methylated forms of the natural amino acids and unnatural amino acids, and the like.

Examples of the substituent which may be substituted on (the side chain of) these amino acid residues include (1) a C _1-6 alkyl group (eg, methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, sec-butyl, tert-
Butyl, n-pentyl, etc., preferably C _1-3 alkyl, etc., (2) cyano group, (3) halogen (eg, fluorine, chlorine, bromine, iodine, etc.), (4) hydroxy-C _1-6 alkyl Groups (eg, hydroxymethyl, hydroxyethyl, etc.), (5) C _1-6 alkoxy groups (eg, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
(6) C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl and the like, preferably C ₁ -butoxy and the like, preferably C _1-3 alkoxy and the like). ₃ alkoxy-carbonyl, etc.), (7) C _1-4
Acyl groups (eg, formyl such as formyl, acetyl, propionyl, butyryl and C _2-4 alkanoyl), (8) hydroxy group, (9) formula: —S (O) a-R ²¹ (where a is A group represented by an integer of 0 to 2 and R ²¹ represents C _1-6 alkyl (specific examples include the same as those described above) (eg, methylthio, methanesulfinyl, methanesulfonyl, ethylthio, ethane) Sulfinyl, ethanesulfonyl, etc.), (10) benzyloxycarbonyl,
(11) tosyl group, (12) carbamoyl group, (13) mercapto group, (14) amino group, (15) sulfo group, (16) phosphono group, (1
7) phospho group, (18) carboxyl group, (19) tetrazolyl group, (20) amino -C _1-6 alkyl group (e.g., aminomethyl, aminoethyl, etc.), (21) amino allyl group, (22) a thiazolyl group , (23) thienyl group, (24) oxazolyl group, (2
5) furyl group, (26) pyranyl group, (27) pyridyl group, (28) pyrazyl group, (29) pyrazinyl group, (30) pyrimidinyl group, (3
1) pyridazinyl group, (32) indolyl group, (33) indozinyl group, (34) isoindolyl group, (35) pyrrolyl group, (36)
Imidazolyl group, (37) isothiazolyl group, (38) pyrazolyl group, (39) chromenyl group, (40) purinyl group, (41) quinolizinyl group, (42) quinolyl group, (43) isoquinolyl group, (44)
Quinazolinyl group, (45) quinoxalinyl group, (46) cinnolinyl group, (47) morpholinyl group, (48) benzothienyl group,
(49) benzofuranyl group, (50) benzimidazolyl, (5
1) benzimidazolyl group, (52) C _3-8 cycloalkyl group, (53) oxo group, (54) above (2), (3), (5) to (19),
(22) to (52) a C _1-4 alkyl group substituted with the substituent described in (52), (55) above (2), (3), (5) to (19), (22) to (5)
Formyl substituted with the substituents described _2), C 2 _-4 C _1-4 acyl group such as an alkanoyl, (56) above (1) to have been such as phenyl substituted with substituents as described for (52) A C _6-10 aryl group (mesityl, tolyl, xylyl, styrenyl, etc.),
(57) _C7-15 aralkyl groups such as benzyl substituted with the substituents described in the above (1) to (52) (methylbenzyl, methoxybenzyl and the like), and (58) _C7-15 aralkyl groups (benzyl, Phenethyl, benzhydryl, naphthylmethyl, etc.), (59) C _6-10 aryl group (phenyl, naphthyl, indenyl, etc.), (60) arginyl group, (61) histidyl group and (62) arginyl-arginyl group. . Examples of the neutral substituent include (1) a C _1-6 alkyl group (eg,
Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and the like, preferably _C1-3 alkyl and the like, (2) cyano group, (3) halogen ( For example, fluorine, chlorine,
(4) hydroxy-C _1-6 alkyl group (eg, hydroxymethyl, hydroxyethyl, etc.),
(5) a hydroxy group, (6) a carbamoyl group, (7) a mercapto group, (8) a group represented by the formula: -S (O) a-R ²¹ (wherein each symbol is as defined above), (9) C _6-10 aryl group (eg, phenyl, naphthyl, indenyl, chromenyl, etc.), (10) thienyl group, (11) oxazolyl group, (12) furyl group, (13) indolyl group, (14) indolizinyl group , (15) isoindolyl group, (16) C _3-8 cycloalkyl group, (17) oxo group, (1
8) above (2), (3), (substituted with a substituent described in 5) (16) a C _1-6 alkyl, the substituents according to (16) from (19) above (1) substituted phenyl, C _6-10 aryl groups such as naphthyl (mesityl, tolyl, xylyl, etc. styrenyl), C ₇ such as benzyl substituted by the substituents described in (16) from (20) above (1) _{And -15} aralkyl groups (methylbenzyl, methoxybenzyl, etc.). As the acidic substituent, a carboxyl group, a sulfo group,
Examples thereof include a C _1-4 alkyl group substituted with a tetrazolyl group, a C _6-10 aryl group such as phenyl and naphthyl, a C _7-15 aralkyl group such as benzyl, and a carboxyl group. As the basic substituent, (1) amino-C _1-6
Alkyl group (aminomethyl, aminoethyl, etc.), (2)
Amino allyl group, (3) pyridyl group, (4) pyrazyl group, (5)
Pyrazinyl group, (6) pyridazinyl group, (7) imidazolyl group, (8) pyrazolyl group, (9) pyrazolyl group, (10) morpholinyl group, (11) amino group, (12) above (3) to (10) A C _1-4 alkyl group substituted with the substituent described in (13), C13 such as benzyl substituted with the substituent described in the above (1) to (11).
_7-15 aralkyl groups, (14) C _6-10 aryl groups such as phenyl and naphthyl substituted with the substituents described in the above (1) to (11), (15) arginyl group, (16) histidyl group and (1
7) Arginyl-arginyl group and the like.

In the present specification, acidic amino acids (residues)
Specific examples include amino acids having an acidic group such as a carboxyl group, a sulfo group, or a tetrazolyl group in a side chain. Specific examples thereof include glutamic acid, pyroglutamic acid, aspartic acid, cysteic acid, homocysteic acid, 3- (5-tetrazolyl) alanine, and 2-amino-4- (5-tetrazolyl) butyric acid. In the present specification, examples of the basic amino acid (residue) include histidine, arginine, ortinine, lysine, diaminopropionic acid, diaminobutyric acid, homoarginine and the like. The side chain is substituted basic amino acids (residues) include, for example, N ^alpha - acetyl arginine, N ^epsilon - tosyl-arginine, N ^epsilon - acetyllysine, N ^epsilon - methyllysine, N ^epsilon - Toshirurijin And so on. In the present specification, as the neutral amino acid (residue), specifically,
For example, alanine, valine, norvaline, leucine,
Isoleucine, alloisoleucine, norleucine, tertiary leucine, gamma methylleucine, proline,
Examples include amino acids such as phenylglycine, phenylalanine, glutamine, asparagine, serine, threonine, glycine, cysteine, methionine, tryptophan, oxyproline (hydroxyproline), cyclohexylalanine, and naphthylalanine. In the present specification, as the amino acid (residue) having an aromatic side chain, specifically, for example, tryptophan, phenylalanine, tyrosine, 1-naphthylalanine, 2-naphthylalanine, 2-thienylalanine, histidine , Pyridylalanine (2-pyridylalanine), O-methyltyrosine and the like. Specific examples of the amino acid (residue) having an aromatic side chain with a substituted side chain include 3-iodotyrosine, p-phosphonomethylphenylalanine, O-phosphotyrosine and the like. In the present specification, examples of the amino acid (residue) having a hydroxy group in a side chain include, for example, serine, threonine,
Tyrosine, oxyproline (hydroxyproline) and the like. In the present specification, a peptide and a peptide chain have an N-terminus (amino terminus) at the left end and a C-terminus (carboxyl terminus) at the right end according to the convention of peptide labeling.
The peptides and peptide chains of the present invention usually have a carboxyl group (—COOH) or a carboxylate (—COO ⁻ ) at the C terminus, but have an amide (—CONH ₂ ) or ester (—COH ₂ ) at the C terminus.
OR). As R of the ester, for example, methyl, ethyl, n-propyl, isopropyl or n
A C _1-6 alkyl group such as -butyl, a C _3-8 cycloalkyl group such as cyclopentyl and cyclohexyl, a phenyl, a C _6-12 aryl group such as α-naphthyl, benzyl,
In addition to phenyl-C _1-2 alkyl such as phenethyl and benzhydryl, or C _7-14 aralkyl groups such as α-naphthyl-C _1-2 alkyl such as α-naphthylmethyl,
Examples include pivaloyloxymethyl groups commonly used as oral esters. When the peptide of the present invention has a carboxyl group or a carboxylate other than at the C-terminus, those in which those groups are amidated or esterified are also included in the polypeptide of the present invention. As the ester at this time, for example, the above-mentioned C-terminal ester and the like are used. In the peptide or peptide chain of the present invention, the amino group of the N-terminal amino acid residue is substituted with a substituent (for example, a C _2-6 alkanoyl group such as formyl or acetyl, guanidinoacetyl, thienylacrylyl, pyridylacetyl, etc.). C _1-8 acyl group, methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, sec-
C such as butyl, tert-butyl, pentyl and hexyl
_1-6 alkyl group, phenyl, C _6-10 aryl group such as naphthyl or benzyl, C _7-16 aralkyl group such as phenethyl, tosyl group, benzyloxycarbonyl group,
Formula: -S (O) a-R 22 ( wherein, a is an integer of 0 to 2, R ²² is C _1-6 alkyl (specific examples include the same can be mentioned) and above) in Groups represented (eg, methylthio, methanesulfinyl, methanesulfonyl, ethylthio, ethanesulfinyl, ethanesulfonyl, etc.),
t-butoxycarbonyl group, N-9-fluorenylmethoxycarbonyl group, etc.), N-terminal glutamine residue formed by cleavage in vivo, pyroglutamine oxidation, amino acid in the molecule substituent (e.g. -OH, -SH, amino group, imidazolyl group, indolyl group, guanidino group, etc.) on the side chain of a suitable protecting group (e.g., formyl group, a C _1-6 alkanoyl group such as acetyl group those are the protected C _1-6 an acyl group), or sugar chains are also conjugated proteins such as glycoproteins bound.

The above formula P1-Arg-Pro-Arg-Leu-Phe-P2-P3-Gly-Pro-P4-P5 (I), formula Q1-Arg-Pro-Arg-Leu-Ser-Ala-Q2- Gly-Q5-Q3-Q4 (II), and each amino acid residue in the formula R1-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-R2-Pro-R3 (III) Side chain) may be substituted
In addition, examples of the substituent include the above-mentioned substituents.
In the present specification, P1, Q1 and R1 represent a “hydrogen atom
Or the same or different side chains are substituted
An amino acid residue consisting of 1 to 25 amino acids
Group or peptide chain ". The "side chain is substituted
1 to 25 amino acids which may be "
For example, for example, the above "substitution to the side chain of the amino acid residue
Substituents which may be substituted "and the like.
P1, Q1 and R1 may be “the side chain may be substituted
Preferred examples of "amino acid residue" include, for example,
An optionally substituted pyroglutamic acid or side chain
Is optionally substituted glutamine and the like.
More preferably, such as pyroglutamic acid or glutamine
Is raised. The "amino optionally substituted in the side chain"
Acid residue "," optionally substituted pyroglutamine
Acid '' and `` glutamine whose side chain may be substituted ''
Examples of the substituent of the amino acid residue include, for example,
"Substituents which may be substituted on the side chains of amino acid residues"
And the like. In addition, "It has been replaced
Preferred substituents of `` pyroglutamic acid may be
A benzyloxycarbonyl group; P1,
Q1 and R1 are the same or different, respectively,
Consists of 2 to 25 amino acids which may be substituted
Specific examples of a `` peptide chain '' include, for example,
Formula Y<sup>1</sup>-Y<sup>Two</sup>(Where Y<sup>1</sup>Are the same or different
1 to 17 amino acids whose side chains may be substituted
An amino acid residue or a peptide chain consisting of <sup>Two</sup>Is
The same or different side chains may be substituted
An amino acid residue consisting of 1 to 8 amino acids or
Peptide chain).
You. Y above<sup>1</sup>And Y<sup>Two</sup>An amino acid residue or pair represented by
Examples of the substituent on the side chain of the amino acid residue in the peptide chain include:
For example, the above-mentioned `` may be substituted on the side chain of an amino acid residue.
And the like.

The above Y¹As a specific example,
If (a) equation A¹-A^Two-A^Three-A^Four-A^Five-A⁶-A⁷-A⁸
-A⁹-A^Ten-A¹¹-A¹²-A ¹³-A¹⁴-A^Fifteen-A¹⁶−
A¹⁷(Where A¹Or A¹⁷Are the same or different
Indicates an amino acid residue whose side chain may be substituted.
), (B) Formula A^Two-A^Three-A^Four-A^Five-A⁶-A⁷-A⁸-A
⁹-A^Ten-A¹¹-A¹²-A¹³-A¹⁴-A^Fifteen-A¹⁶-A¹⁷
(Wherein each symbol is as defined above), (c) Formula A^Three−
A^Four-A^Five-A⁶-A⁷-A⁸-A⁹-A^Ten-A¹¹-A¹²-A
¹³-A¹⁴-A^Fifteen-A¹⁶-A¹⁷(In the formula, each symbol is the same as above.
(D) Significance), (d) Formula A^Four-A^Five-A⁶-A⁷-A⁸-A⁹
-A^Ten-A¹¹-A¹²-A¹³-A¹⁴-A^Fifteen-A¹⁶-A
¹⁷(Wherein each symbol has the same meaning as described above), (e) Formula A^Five
-A⁶-A⁷-A⁸-A⁹-A^Ten-A¹¹-A¹²-A¹³-A¹⁴
-A^Fifteen-A¹⁶-A¹⁷(Wherein each symbol is as defined above)
), (F) Formula A⁶-A⁷-A⁸-A⁹-A^Ten-A¹¹-A¹²
-A¹³-A¹⁴-A^Fifteen-A¹⁶-A^{1 7}(Wherein each symbol is
And (g) Formula A⁷-A⁸-A⁹-A^Ten-A¹¹
-A¹²-A¹³-A¹⁴-A^Fifteen-A¹⁶-A¹⁷(In the formula, each symbol
Is as defined above), (h) Formula A⁸-A⁹-A^Ten-A
¹¹-A¹²-A¹³-A¹⁴-A^Fifteen-A¹⁶-A¹⁷(In the formula, each note
Are as defined above), (i) Formula A⁹-A^Ten-A¹¹−
A¹²-A¹³-A¹⁴-A^Fifteen-A¹⁶-A¹⁷(Where each symbol is
The meaning is as defined above), (j) Formula A^Ten-A¹¹-A¹²-A
¹³-A¹⁴-A^Fifteen-A¹⁶-A¹⁷(In the formula, each symbol is the same as above.
Significance), (k) Formula A¹¹-A¹²-A¹³-A¹⁴-A^Fifteen
-A¹⁶-A¹⁷(Wherein each symbol is as defined above),
(l) Equation A¹²-A¹³-A¹⁴-A^Fifteen-A¹⁶-A¹⁷(Where
Each symbol is as defined above), (m) Formula A¹³-A¹⁴−
A^Fifteen-A¹⁶-A¹⁷(Wherein each symbol is as defined above)
A), (n) Expression A¹⁴-A^Fifteen-A¹⁶-A¹⁷(In the formula, each symbol
Is as defined above), (0) Formula A^Fifteen-A¹⁶-A
¹⁷(Wherein each symbol is as defined above), (p) Formula A
¹⁶-A¹⁷(Wherein each symbol is as defined above) or
(q) A¹⁷(A¹⁷Is as defined above)
Noic acid residues or peptide chains.

A ¹ represents an amino acid residue whose side chain may be substituted, but is preferably an amino acid residue having an aromatic side chain, more preferably an L-amino acid residue having an aromatic side chain. Amino acid residues, more preferably L-tyrosine and the like. A ² and A ³ are the same or different and each represents an amino acid residue whose side chain may be substituted, preferably a neutral amino acid residue whose side chain may be substituted, more preferably , the side chain may be substituted L- neutral amino acid residues, more preferably as the A ² L- leucine, etc., as the A ^3, etc. L- valine. The A ⁴ represents an amino acid residue may be substituted side chain, but preferably, be neutral or basic amino acid residue whose side chain may be substituted, more preferably, the side chain is replaced And L-neutral or L-basic amino acid residues, more preferably L-lysine or ^Nε -acetyllysine. The A ⁵ are but represents an amino acid residue which may be substituted side chain, preferably, be a neutral amino acid residue whose side chain may be substituted, more preferably, it may be substituted L- Proline, more preferably L-proline and the like. A ⁶ and A ⁹ are the same or different and each represents an amino acid residue whose side chain may be substituted, but is preferably a basic amino acid residue whose side chain may be substituted, more preferably And L-basic amino acid residues whose side chains may be substituted, more preferably L-arginine.
The A ⁷ and A ¹⁰ is independently an identical or different side chain amino acid residue may be substituted, preferably, amino acid residue or side chain having a hydroxy group in the side chain substituted Or a good neutral amino acid residue. A ⁷ represents glycine which may be substituted,
Particularly, glycine and the like are preferably used. A ⁸ represents an amino acid residue whose side chain may be substituted, but is preferably L-proline or an amino acid residue having a hydroxy group in the side chain, more preferably L-serine, L-proline or Oxyproline (hydroxyproline) and the like. As preferably the A ^10, good neutral amino acid residue whose amino acid residue or side chain having a hydroxy group in the side chain may be substituted, more preferably shows serine, threonine, asparagine and the like. A ¹¹ to A ¹⁴ are the same or different and each represents an amino acid residue whose side chain may be substituted, preferably a neutral amino acid residue whose side chain may be substituted, more preferably , A ¹¹
The glycine, as A ¹² is L- proline as the A ¹³ glycine, as the A ¹⁴ L- alanine and L- proline and the like. A ¹⁵ represents an amino acid residue whose side chain may be substituted, but is preferably an amino acid residue having an aromatic side chain, and more preferably an L-amino acid having an aromatic side chain. Residue, more preferably L
-Indicates tryptophan and the like. A ¹⁶ represents an amino acid residue whose side chain may be substituted, preferably a neutral amino acid residue whose side chain may be substituted, more preferably a neutral L-amino acid having a carbamoyl group. Amino acid residues,
More preferably, L-glutamine is used. Examples of the neutral L-amino acid residue having a carbamoyl group include L-glutamine and L-asparagine. A ¹⁷ represents an amino acid residue whose side chain may be substituted, preferably a neutral amino acid residue whose side chain may be substituted, more preferably glycine or the like.

As a specific example of the above Y ² , for example, a compound represented by the formula B ¹ -B ² -B ³ -B ⁴ -B ⁵ -B ⁶ -B ⁷ -B ⁸ (wherein B ¹ to B ⁸ are The same or different amino acid residues whose side chains may be substituted), a formula B ² -B ³ -B ⁴ -B ⁵ -B ⁶ -B ⁷ -B ⁸ (wherein each symbol is as defined above) as defined shows a), wherein ^{B 3 -B 4 -B 5 -B 6} -B 7 -B 8 ( wherein each symbol is as defined above), the formula B ⁴ -B ⁵ -B ⁶ -B ⁷ -B ⁸ (wherein each symbol is as defined above), the formula ^{B 5 -B 6 -B 7 -B 8} ( wherein each symbol is as defined above), the formula B ⁶ - B ⁷ -B ⁸ (wherein each symbol is as defined above), the formula B ⁷ -B ⁸ (wherein each symbol is as defined above)
Or an amino acid residue or a peptide chain represented by the formula B ⁸ (B ⁸ is as defined above). B ¹ above
Represents an amino acid residue whose side chain may be substituted,
Preferably, a neutral amino acid residue whose side chain may be substituted, more preferably, a neutral L-amino acid residue whose side chain may be substituted, still more preferably, glycine which may be substituted , Most preferably glycine or the like. B ² to B ⁴ are the same or different,
It shows an amino acid residue whose side chain may be substituted, but is preferably a basic amino acid residue whose side chain may be substituted, more preferably a basic amino acid residue whose side chain may be substituted. - amino acid residues, more preferably, the B ² L- arginine, as the B ³ L- arginine, as the B ^4, indicating, for example, L- lysine. It said B ⁵ represents an amino acid residue may be substituted side chain, but preferably,
An amino acid residue having an aromatic side chain, more preferably an L-amino acid residue having an aromatic side chain, and still more preferably L-phenylalanine. B above
⁶ and B ^7, the same or different, and represent an amino acid residue whose side chain may be substituted, preferably,
A basic amino acid residue whose side chain may be substituted, more preferably a basic L-amino acid residue whose side chain may be substituted, further preferably L-arginine and the like. The B ⁸ represents an amino acid residue may be substituted side chain, preferably, an optionally side chain is substituted glutamine, more preferably, indicating, for example, L- glutamine.

As a combination of Y ¹ and Y ² , (a)
If the formula represented by in represented by the formula + above (i.e. X ^{1 is, A 1 -A 2 -A 3 -A} 4 -A 5 -A 6 -A 7 -A 8 -
A ⁹ -A ¹⁰ -A ¹¹ -A ¹² -A ¹³ -A ¹⁴ -A ¹⁵ -A ¹⁶ -A
¹⁷ -B ¹ -B ² -B ³ -B ⁴ -B ⁵ -B ⁶ -B ⁷ -B ⁸ : omitted in the description of the following combinations), and represented by (a) above When represented by the formula + the formula represented by the above, the formula represented by the above (a) + by the formula represented by the above, the formula represented by the above (a) + the represented by the above When represented by the above formula, when represented by the above formula (a) + by the above formula, represented by the above formula (a) + the above formula In the case, when represented by the expression represented by the above (a) + the expression represented by the above, the above (a)
In the case of being represented by the formula represented by the above + the formula represented by the above, the formula represented by the above (b) + in the case of being represented by the above formula, the formula represented by the above (b) + When represented by the formula represented above, the formula represented by the above (b) + when represented by the formula represented by the above, the formula represented by the above (b) + the formula represented by the above When represented by the above, the expression represented by the above (b) + when represented by the above expression, the expression represented by the above (b) +
When represented by the formula represented above, the formula represented by the above (b) + when represented by the formula represented by the above, the formula represented by the above (b) + the formula represented by the above When represented by the above
When represented by the formula represented by (c) + the formula represented by the above, when represented by the formula represented by the above (c) + the formula represented by the above, represented by the above (c) In the case of being represented by the formula represented by the above formula, the formula represented by the above (c) + the formula represented by the above formula, the formula represented by the above (c) + the formula represented by the above formula When the expression is expressed by the following expression, the expression expressed by the above (c) +
When represented by the above-described formula, when represented by the above-described (c) formula + when represented by the above-described formula, the above-described formula represented by the above (c) + the above-described formula When represented by the above
When represented by the formula represented by (d) + the formula represented by the above, when represented by the formula represented by the above (d) + the formula represented by the above, represented by the above (d) In the case of being represented by the above formula + the above formula, the above formula (d) + the above formula (d), the above formula (d) + the above formula In the case of being expressed by the following expression, the expression expressed by the above (d) +
When represented by the formula represented above, the formula represented by the above (d) + when represented by the formula represented by the above, the formula represented by the above (d) + the formula represented by the above When represented by the above
When represented by the formula represented by (e) + the formula represented by the above, when represented by the formula represented by the above (e) + the formula represented by the above, represented by the above (e) In the case of being represented by the formula represented by the above formula, the formula represented by the above (e) + the formula represented by the above formula, the formula represented by the above (e) + the formula represented by the above formula In the case of being represented by the following expression, the expression represented by the above (e) +
When represented by the above-described formula, when represented by the above-described (e) formula + when represented by the above-described formula, the above-described formula represented by (e) + the above-described formula When represented by the above
When represented by the formula represented by (f) + the formula represented by the above, when represented by the formula represented by the above (f) + the formula represented by the above, represented by the above (f) In the case of being represented by the formula represented by the above formula, the formula represented by the above (f) + the formula represented by the above formula, the formula represented by the above (f) + the formula represented by the above formula When the expression is expressed by the following expression, the expression expressed by the above (f) +
When represented by the formula represented above, the formula represented by the above (f) + when represented by the formula represented by the above, the formula represented by the above (f) + the formula represented by the above When represented by the above
When represented by the formula represented by (g) + the formula represented by the above, when represented by the formula represented by the above (g) + the formula represented by the above, represented by the above (g) In the case of being represented by the above formula + the above formula, the above formula (g) + the above formula (g), the above formula (g) + the above formula In the case of being represented by the following expression, the expression represented by the above (g) +
When represented by the above-described formula, when represented by the above-described (g) + when represented by the above-described formula, the above-described formula represented by the above (g) + the above-described formula When represented by the above
When represented by the formula represented by (h) + the formula represented by the above, when represented by the formula represented by the above (h) + the formula represented by the above, represented by the above (h) In the case of being represented by the above formula + the above formula, the above formula (h) + in the case of the above formula, the above formula (h) + the above formula When the expression is expressed by the following expression, the expression expressed by the above (h) +
When represented by the formula represented above, the formula represented by the above (h) + when represented by the formula represented by the above, the formula represented by the above (h) + the formula represented by the above When represented by the above
When represented by the formula represented by (i) + the formula represented by the above, when represented by the formula represented by the above (i) + the formula represented by the above, represented by the above (i) In the case of being represented by the expression represented by the above expression, the expression represented by the above (i) + the expression represented by the above expression, the expression represented by the above (i) + the expression represented by the above In the case of being represented by the following expression, the expression represented by the above (i) +
When represented by the above formula, when represented by the above (i) + by the above formula, when represented by the above (i) + formula represented by the above When represented by the above
When represented by the expression represented by (j) + the expression represented by the above, when represented by the expression represented by the above (j) + the expression represented by the above, represented by the above (j) In the case of being represented by the above expression + the expression of the above, the expression of the above (j) + in the case of being represented by the above expression, the expression of the above (j) + the above expression When the expression is expressed by the following expression, the expression expressed by the above (j) +
When represented by the above formula, when represented by the above (j) + by the above formula, when represented by the (j) formula + by the above formula When represented by the above
When represented by the formula represented by (k) + the formula represented by the above, when represented by the formula represented by the (k) + the formula represented by the above, represented by the above (k) In the case of being represented by the above expression + the expression of the above, the expression of the above (k) + in the case of being represented by the above expression, the expression of the above (k) + the above expression When the expression is expressed by the following expression, the expression expressed by the above (k) +
When represented by the above-described formula, when represented by the above-described (k) + when represented by the above-described formula, the above-described formula represented by (k) + the above-described formula When represented by the above
When represented by the formula represented by (l) + the formula represented by the above, when represented by the formula represented by the above (l) + the formula represented by the above, represented by the above (l) In the case of being represented by the above formula + the above formula, the formula of the above (l) + in the case of the above formula, the above formula of the (1) + the above formula When the expression is expressed by the following expression, the expression expressed by the above (l) +
When represented by the above-described formula, when represented by the above-described formula (l) + when represented by the above-described formula, the formula represented by the above-mentioned (l) + the formula represented by the above When represented by the above
When represented by the formula represented by (m) + the formula represented by the above, when represented by the formula represented by the above (m) + the formula represented by the above, represented by the above (m) In the case of being represented by the formula represented by the above formula, the formula represented by the above (m) + the formula represented by the above formula, the formula represented by the above (m) + the formula represented by the above When the expression is expressed by the following expression, the expression expressed by the above (m) +
When represented by the above formula, when represented by the above (m) + by the above formula, the formula represented by the (m) + formula represented by the above When represented by the above
When represented by the formula represented by (n) + the formula represented by the above, when represented by the formula represented by the above (n) + the formula represented by the above, represented by the above (n) In the case of being represented by the above formula + the above formula, the above formula (n) + the above formula (n), the above formula (n) + the above formula When the expression is expressed by the following expression, the expression expressed by the above (n) +
When represented by the above formula, when represented by the above (n) + formula represented by the above, the formula represented by the above (n) + formula represented by the above When represented by the above
When represented by the formula represented by (o) + the formula represented by the above, when represented by the formula represented by the above (o) + the formula represented by the above, represented by the above (o) In the case of being represented by the above formula + the above formula, the above formula (o) + the above formula (o), the above formula (o) + the above formula In the case of being represented by the following expression, the expression represented by the above (o) +
When represented by the above formula, when represented by the above (o) formula, when represented by the above formula, the formula represented by the above (o) formula + the formula represented by the above formula When represented by the above
When represented by the formula represented by (p) + the formula represented by the above, when represented by the formula represented by the above (p) + the formula represented by the above, represented by the above (p) In the case of being represented by the formula represented by the above formula, the formula represented by the above (p) + the formula represented by the above formula, the formula represented by the above (p) + the formula represented by the above formula When the expression is expressed by the following expression, the expression expressed by the above (p) +
When represented by the above formula, when represented by the above (p) formula, when represented by the above formula, the formula represented by the above (p) + formula represented by the above formula When represented by the above
When represented by the formula represented by (q) + the formula represented by the above, when represented by the formula represented by the above (q) + the formula represented by the above, represented by the above (q) In the case of being represented by the above expression + the expression represented by the above, the expression represented by the above (q) + in the case of being represented by the above expression, the expression represented by the above (q) + the above expression When the expression is expressed by the following expression, the expression expressed by the above (q) +
When represented by the formula represented by the above, when represented by the formula represented by the above (q) + the formula represented by the above, and
There is a case where it is represented by the expression represented by (q) + the expression represented by the above,

In particular, when the above equation (a) + the above equation is used, the above equation (b) +
When represented by the above formula, when represented by the above formula (c) + when represented by the above formula, the formula represented by the above (d) + formula represented by the above If represented by
When represented by the formula represented by (e) + the formula represented by the above, when represented by the formula represented by the above (f) + the formula represented by the above, represented by the above (g) In the case of being represented by the above formula + the above formula, the above formula (h) + the above formula (i), the above formula (i) + the above formula When the expression is expressed by the following expression, the expression expressed by the above (j) +
When represented by the above formula, when represented by the above (k) + when represented by the above formula, the formula represented by the above (l) + formula represented by the above When represented by the above
When represented by the formula represented by (m) + the formula represented by the above, when represented by the formula represented by the above (n) + the formula represented by the above, represented by the above (o) In the case of the expression represented by the above expression, the expression of the above (p) + the expression of the above expression, and the expression of the above (q) +
The case represented by the above formula is preferred. Among them, more preferred examples are the case represented by the formula represented by the above (a) + the formula represented by the above and the case represented by the formula represented by the above (b) + the formula represented by the above. As More preferable specific examples of the case represented by the formula represented by the formula (a) + the formula represented by the above and the formula represented by the formula (b) + the formula represented by the above are described below. Shown in The case where P1, Q1 and / or R1 are represented by the formula A ^{2
-A 3 -A 4 -A 5 -A 6} -A 7 -A 8 -A 9 -A 10 -A 1 1 -
A ¹² -A ¹³ -A ¹⁴ -A ¹⁵ -A ¹⁶ -A ¹⁷ -B ¹ -B ² -B ³
-B ⁴ -B ⁵ -B ⁶ -B ⁷ -B ⁸ (wherein A ² to A ¹⁷ and B ¹ to B ⁸ have the same meanings as described above). Preferred specific examples of the case include:
A ² and A ³ are the same or different, and an L-neutral amino acid residue whose side chain may be substituted, preferably A ² is L-leucine or the like, and A ³ is L-valine or the like. , A ⁴ is the side chain may be substituted L- neutral or L- basic amino acid residue, preferably L- glutamine, L- lysine or N ^epsilon - and the like acetyl lysine, A ⁵ is the side chain Is optionally substituted L-proline,
Preferably, and the like L- proline, A ⁶ and A ⁹ are the same or different, side chain may be substituted L- basic amino acid residues, and the like preferably L- arginine, A ⁷ Is optionally substituted glycine,
Preferably, glycine or the like, A ⁸ is L-proline or an amino acid residue having a hydroxy group in a side chain, preferably L-serine, L-proline or oxyproline (hydroxyproline), and A ¹⁰ is An amino acid residue having a hydroxy group in the side chain or a neutral amino acid residue in which the side chain may be substituted, preferably L-serine, L-threonine, L-asparagine and the like;
¹¹ is glycine, A ¹² is L-proline, A ¹³ is glycine,
And the like A ¹⁴ is L- alanine or L- proline, A ¹⁵
Is an L-amino acid residue having an aromatic side chain, preferably L-tryptophan, etc., A ¹⁶ is a neutral L-amino acid residue having a carbamoyl group, preferably L-glutamine, and A ¹⁷ is A neutral amino acid residue, preferably glycine or the like, wherein B ¹ is a neutral L-amino acid residue whose side chain may be substituted, preferably glycine optionally substituted, more preferably glycine; And so on,
B ² to B ⁴ are the same or different and each may be a basic L-amino acid residue which may be substituted in the side chain, preferably, B ² is L-arginine, B ³ is L-arginine, B ⁴ Is L-lysine or the like, and B ⁵ is an L-amino acid residue having an aromatic side chain, preferably
And the like L- phenylalanine, B ⁶ and B ⁷ are the same or different, whose side chain may be substituted basic L- amino acid residue, preferably, L- arginine and the like, B ⁸ is a side Examples include glutamine whose chain may be substituted, preferably L-glutamine and the like.

[0018] the case of the formula represented by the formula + above represented by the above (a) is, X ¹ has the formula ^{A 1 -A 2 -A 3 -A 4} -
^{A 5 -A 6 -A 7 -A 8} -A 9 -A 10 -A 11 -A 12 -A 13 -
A ¹⁴ -A ¹⁵ -A ¹⁶ -A ¹⁷ -B ¹ -B ² -B ³ -B ⁴ -B ^5-
B ⁶ -B ⁷ -B ⁸ (wherein, A ¹ to A ¹⁷ and B ¹ to B ⁸ have the same meanings as described above). Preferred specific examples in this case are: , A ¹ is an L-amino acid residue having an aromatic side chain, more preferably L
-Tyrosine or the like, wherein A ² and A ³ are the same or different, and an L-neutral amino acid residue whose side chain may be substituted, preferably A ² as L-leucine, and A ³ as A ³ L- valine and the like, A ⁴ is the side chain may be substituted L- neutral or L- basic amino acid residue, preferably L- glutamine, L-alpha-aminoadipic acid, L- lysine or N ^ε -acetyl lysine, etc., wherein A ⁵ is L-proline which may be substituted, preferably L-proline, etc., wherein A ⁶ and A ⁹ are the same or different, and the side chain is substituted. Good L-
A basic amino acid residue, preferably L-arginine, etc., wherein A ⁷ is an optionally substituted glycine, preferably glycine, etc., and A ⁸ is L-proline or an amino acid residue having a hydroxy group in a side chain; , Preferably L-
Serine, L- proline or the like oxyproline (hydroxyproline), A ¹⁰ is a good neutral amino acid residue whose amino acid residue or side chain having a hydroxy group in the side chain may be substituted, preferably L- serine , L-threonine, L-asparagine and the like, wherein A ¹¹ is glycine,
A ¹² is L-proline, A ¹³ is glycine, A ¹⁴ is L-alanine or L-proline, and A ¹⁵ is an L-amino acid residue having an aromatic side chain, preferably L-tryptophan or the like. A neutral L in which A ¹⁶ has a carbamoyl group
An amino acid residue, preferably L-glutamine,
¹⁷ is a neutral amino acid residue, preferably glycine or the like; B ¹ is a neutral L-amino acid residue whose side chain may be substituted, preferably glycine which may be substituted;
More preferably, it is glycine or the like, wherein B ² to B ⁴ are the same or different, and a basic L-amino acid residue which may have a substituted side chain, preferably B ² is L-arginine, B the ³ L- arginine, as the B ^4, and the like L- lysine, L- amino acid residue B ⁵ has an aromatic side chain, preferably, L- phenylalanine and the like, B ⁶ and B ⁷ is the same or different, and each is a basic L-amino acid residue whose side chain may be substituted, preferably L-arginine,
Examples include the case where B ⁸ is glutamine whose side chain may be substituted, preferably L-glutamine L-pyroglutamic acid and the like.

Preferred examples of P1, Q1 and R1 are (1) hydrogen atom, (2) Arg-Gln, (3) Arg, (4)
Gln, (5) pGlu, or (6) Arg-Arg-Gln and the like. Further, as P1, a hydrogen atom, pGlu or
Arg-Arg-Gln is more preferred, and Q1 is more preferably a hydrogen atom, pGlu or Arg-Arg-Gln;
Is more preferably a hydrogen atom, pGlu or Arg-Arg-Gln (furthermore, a hydrogen atom or Arg-Arg-Gln). In the present specification, P2 represents a neutral amino acid residue in which the side chain may be substituted or a basic amino acid residue in which the side chain may be substituted. L-alanine which may be substituted, L-histidine which may be substituted (in a side chain) and the like. In the present specification, P3 and Q2 represent a neutral amino acid residue whose side chain may be substituted, an aromatic amino acid residue whose side chain may be substituted, or a base whose side chain may be substituted Shows amino acid residues. Examples of the substituent on the side chain of the basic amino acid residue include a C _1-4 acyl group, a tosyl group, and a C _1-6
And an alkyl group. Examples of the C _1-4 acyl group include formyl, acetyl, propionyl, butyryl and the like, and C _2-4 alkanoyl.
Examples of the C _1-6 alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like. P3 and Q2 are preferably L-lysine in which the side chain may be substituted, L-norleucine in which the side chain may be substituted, or L-arginine in which the side chain may be substituted. More preferably, the side chain is a C _1-4 acyl group (eg, such as formyl, acetyl, propionyl, butyryl and C _2-4 alkanoyl), a C _1-6 alkyl group (eg, methyl, ethyl, propyl, Isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) or L-lysine, L-norleucine or L-arginine which may be substituted with a tosyl group. - lysine, L- norleucine, L- arginine, N ^epsilon - acetyllysine, N ^epsilon - methyllysine,
N ^ε -tosyl lysine, N ^g -tosyl arginine and the like. Further, as P3 and Q2, L-arginine which may be substituted or L-lysine which may be substituted is preferable. In the present specification, P4 and Q3 represent a bond or a neutral amino acid in which a side chain may be substituted or an aromatic amino acid residue in which a side chain may be substituted. P4 and Q3 are preferably a bond,
L-norleucine having an optionally substituted side chain, L-methionine having an optionally substituted side chain, L-methionine sulfoxide having an optionally substituted side chain, or L-methionine sulfoxide having an optionally substituted side chain. Good L-alanine and the like,
More preferably, a bond, L-norleucine, L-methionine, L-methionine sulfoxide, L-cyclohexylalanine and the like can be mentioned. Further, as P4, L-norleucine, L-methionine, L-cyclohexylalanine and the like are particularly preferable. Also, Q3
Is particularly preferably a bond, L-methionine or L-cyclohexylalanine. In the present specification, P5 and Q4 are an amino acid residue whose side chain may be substituted or an amino acid derivative having a C-terminal carboxyl group reduced to a hydroxymethyl group or formyl group, a hydroxyl group or a side chain substituted. A dipeptide chain formed by bonding a good amino acid residue and an amino acid residue whose side chain may be substituted, or a peptide derivative in which the C-terminal carboxyl group is reduced to a hydroxylmethyl group or a formyl group.

P5 and Q4 are preferably neutral amino acid residues whose side chains may be substituted or their C
An amino acid derivative in which a terminal carboxyl group is reduced to a hydroxymethyl group or formyl group, a neutral amino acid residue in which a hydroxyl group or a side chain may be substituted and an aromatic side chain in which a side chain may be substituted And dipeptide chains formed by bonding amino acid residues having the same or peptide derivatives in which the C-terminal carboxyl group is reduced to a hydroxylmethyl group or formyl group. More preferably, P5 and Q4 are L-proline which may have a substituted side chain or an amino acid derivative in which the C-terminal carboxyl group is reduced to a hydroxymethyl group or a formyl group, or the side chain may be substituted. -Chlorophenylalanine or an amino acid derivative having its C-terminal carboxyl group reduced to a hydroxymethyl group or formyl group, 2-naphthylalanine whose side chain may be substituted or its C-terminal carboxyl group being substituted with a hydroxymethyl group or formyl group A reduced amino acid derivative, an amino acid derivative in which a cyclohexylalanine or a C-terminal carboxyl group thereof whose side chain may be substituted is reduced to a hydroxymethyl group or a formyl group,
A hydroxyl group or an optionally substituted L-proline;
(a) L-phenylalanine whose side chain may be substituted, (b) L-tyrosine whose side chain may be substituted, (c)
L-2-thienylalanine in which the side chain may be substituted, (d) L-phenylglycine in which the side chain may be substituted or (e) L-phenyl in which the side chain may be substituted
Examples include a dipeptide chain having 2-pyridylalanine bonded thereto, or a peptide derivative in which the C-terminal carboxyl group has been reduced to a hydroxylmethyl group or a formyl group. More preferably as P5 and Q4,
(1) L-proline or an amino acid derivative whose C-terminal carboxyl group is reduced to a hydroxymethyl group or formyl group; (2) 4-chlorophenylalanine or its C-terminal carboxyl group is reduced to a hydroxymethyl group or formyl group Amino acid derivatives, (3) 2-naphthylalanine or its amino acid derivative whose C-terminal carboxyl group is reduced to a hydroxymethyl group or formyl group, (4) cyclohexylalanine or its C-terminal carboxyl group which is reduced to hydroxymethyl group or formyl group (5) a hydroxyl group, (6) a dipeptide chain formed by bonding L-proline and L-phenylalanine or a peptide derivative in which the C-terminal carboxyl group is reduced to a hydroxylmethyl group or a formyl group, (7) L
A dipeptide chain formed by bonding proline and L-tyrosine or a peptide derivative in which the C-terminal carboxyl group is reduced to a hydroxylmethyl group or a formyl group, (8)
A dipeptide chain formed by bonding L-proline and L-2-thienylalanine or a peptide derivative in which the C-terminal carboxyl group is reduced to a hydroxylmethyl group or a formyl group; (9) L-proline and L-phenylglycine are bonded A dipeptide chain obtained by reducing the C-terminal carboxyl group to a hydroxylmethyl group or a formyl group, or (10) a dipeptide chain formed by bonding L-proline and 4-chlorophenylalanine or the C-terminal carboxyl group Peptide derivative reduced to hydroxylmethyl group or formyl group, (11) Peptide derivative in which dipeptide chain formed by bonding L-proline and 2-naphthylalanine or its C-terminal carboxyl group is reduced to hydroxylmethyl group or formyl group , (12)
A dipeptide chain formed by bonding L-proline and 3-iodotyrosine or a peptide derivative in which the C-terminal carboxyl group is reduced to a hydroxylmethyl group or a formyl group; (13) L-proline bonds to O-methyltyrosine Or a peptide derivative in which the C-terminal carboxyl group thereof is reduced to a hydroxylmethyl group or a formyl group, or (14) a dipeptide chain formed by bonding L-proline and L-2-pyridylalanine, or a C-terminal carboxyl group thereof Is reduced to a hydroxylmethyl group or a formyl group.

"-P4-P5" and "-Q3-Q4"
As particularly preferred, (1) -Nle-Pro-Phe, (2) -Nle
-Pro-Tyr, (3) -Nle-Pro, (4) -Nle, (5) -Met-Pro-Ph
e, (6) -Nle-Pro-Thi, (7) -Nle-Pro-Phg, (8) -Nle-Pr
o-Pya (2), (9) -Met (O), (10) -Met-Phe (Cl), (11) -Me
t-Pro-Phe (Cl), (12) -Met-Pro-Nal (2), (13) -Met-Nal
(2), (14) -Met-Cha, (15) -Cha-Pro-Phe, (16) -Cha,
(17) -Met-Pro-Tyr (I), (18) -Cha-Pro-Phe (Cl), (19)
-Cha-Phe (Cl), (20) -Nle-Pro-Tyr (I), (21) -Nle-Phe
(Cl), (22) -Cha-Pro-Tyr (I), (23) -Cha-Tyr (I), (24)
-Cha-Phe, (25) -Met-Phe, (26) -Met-Pro-Tyr (Me),
(27) -OH, (28) -Met, (29) -Met-Pro-Phe, and (30)
-Ala-Pro-Phe (Cl) and the like. Also, "-P4
-P5 "includes (1) -Cha-Pro-Phe (Cl), (2) -Cha-P
ro-Phe, (3) -Met-Pro-Phe (Cl), (4) -Met-Pro-Phe (5)
-Cha-Phe, and (6) -Met-Phe are preferred, and (1) -Cha-P
ro-Phe (Cl), (2) -Cha-Pro-Phe, (3) -Met-Pro-Phe (C
l), and (4) -Met-Pro-Phe are particularly preferred. further,
"-Q3-Q4" includes (1) -Met-Pro-Phe (Cl),
(2) -Cha-Phe (Cl), (3) -Cha-Pro-Phe (Cl), (4) -Cha,
(5) -Cha-Pro-Phe, (6) -OH, (7) -Met, (8) -Met-Pro-
Phe and (9) -Ala-Pro-Phe (Cl) are particularly preferred.

In the present specification, Q5 represents a neutral amino acid residue whose side chain may be substituted, preferably L-proline which may be substituted, L-glycine which may be substituted or 2 shows L-alanine which may be substituted. Particularly preferred as Q5 is L-proline,
Indicates L-glycine or L-alanine. In the present specification, R2 represents L-cyclohexylalanine which may be substituted, preferably L-cyclohexylalanine. In the present specification, R3 is an optionally substituted L-phenylalanine, an optionally substituted L-phenylalanine.
2-naphthylalanine, optionally substituted L-cyclohexylalanine or optionally substituted tyrosine, preferably L-4-chlorophenylalanine, L-2-naphthylalanine, L-cyclohexylalanine, L-phenylalanine Or L-tyrosine.

Specific examples of the peptide of the present invention include, for example,
If (1) Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-Ala-Arg-G
ly-Pro-Met-Pro-Phe (Cl), (2) Arg-Arg-Gln-Arg-Pro-A
rg-Leu-Ser-His-Lys-Gly-Pro-Cha-Pro-Phe (Cl), (3) A
rg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Met-Pro-Phe (C
l), (4) Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Cha-P
he (Cl), (5) Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-C
ha-Pro-Phe (Cl), (6) Arg-Arg-Gln-Arg-Pro-Arg-Leu-S
er-Ala-Arg-Gly-Pro-Cha, (7) Arg-Pro-Arg-Leu-Ser-H
is-Lys-Gly-Pro-Cha-Pro-Phe (Cl), (8) Arg-Pro-Arg-L
eu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe (Cl), (9) pGlu-
Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Cha-Pro-Phe,
(10) pGlu-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met
-Pro-Phe (Cl), (11) Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gl
y-Pro-Cha-Pro-Phe, (12) Arg-Pro-Arg-Leu-Phe-Ala-A
rg-Gly-Pro-Cha-Pro-Phe (Cl), (13) Arg-Pro-Arg-Leu-
Phe-His-Lys-Gly-Pro-Cha-Pro-Phe (Cl), (14) Arg-Arg
-Gln-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Nle-Pro-T
yr, (15) Arg-Pro-Arg-Leu-Phe-His-Lys-Gly-Pro-Cha-
Pro-Phe, (16) Arg-Pro-Arg-Leu-Phe-His-Lys-Gly-Pro
-Met-Pro-Phe (Cl), (17) Arg-Arg-Gln-Arg-Pro-Arg-Le
u-Ser-Ala-Arg-Gly-Pro-Met-Pro-Phe, (18) Arg-Arg-G
ln-Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Met, (19)
Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro,
(20) Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-
Pro-Met (O), (21) Arg-Arg-Lys (Arg-Arg) -Arg-Pro-A
rg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe, (22) Arg-
Arg-Arg-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pr
o-Phe, (23) Arg-Arg-Lys-Arg-Pro-Arg-Leu-Ser-His-L
ys-Gly-Pro-Met-Pro-Phe, (24) Arg-Pro-Arg-Leu-Ser-
Ala-Arg-Gly-Pro-Met-Pro-Phe, (25) Arg-Arg-Ala-Arg
-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe, (26)
 pGlu-Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Met-Pro
-Phe, (27) Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Me
t, (28) Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-P
he (Cl), (29) pGlu-Arg-Pro-Arg-Leu-Ser-Ala-Lys-Gly
-Pro-Met-Pro-Phe, (30) pGlu-Arg-Pro-Arg-Leu-Ser-A
rg-Lys-Gly-Pro-Met-Pro-Phe, (31) Arg-Pro-Arg-Leu-
Phe-Ala-Arg-Gly-Pro-Met-Pro-Phe, (32) Arg-Pro-Arg
-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Nal (2), (33) Arg
-Arg-Phe-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-P
ro-Phe, (34) pGlu-Arg-Pro-Arg-Leu-Ser-His-Arg-Gly
-Pro-Met-Pro-Phe, (35) pGlu-Arg-Pro-Arg-Leu-Ser-H
is-Lys-Gly-Pro-Met-Phe (Cl), (36) Arg-Pro-Arg-Leu-
Ser-His-Lys-Gly-Pro-Met-Cha, (37) Arg-Pro-Arg-Leu
-Phe-His-Lys-Gly-Pro-Cha-Phe (Cl), (38) pGlu-Arg-P
ro-Arg-Leu-Ser-Leu-Lys-Gly-Pro-Met-Pro-Phe, (39)
pGlu-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-N
al (2), (40) Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-M
et-Nal (2), (41) pGlu-Arg-Pro-Arg-Leu-Ser-Arg-Arg-
Gly-Pro-Met-Pro-Phe, (42) pGlu-Arg-Pro-Arg-Leu-Ph
e-Arg-Arg-Gly-Pro-Met-Pro-Phe, (43) pGlu-Arg-Pro-
Arg-Leu-Ser-Phe-Lys-Gly-Pro-Met-Pro-Phe, (44) pGl
u-Arg-Pro-Arg-Leu-Phe-His-Lys-Gly-Pro-Met-Pro-Ph
e, (45) pGlu-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-
Met-Cha, (46) pGlu-Arg-Pro-Arg-Leu-Ser-His-Lys-Gl
y-Pro-Met-Nal (2), (47) Arg-Pro-Arg-Leu-Phe-Ala-Ar
g-Gly-Pro-Met-Phe, (48) pGlu-Arg-Pro-Arg-Leu-Ser-
His-Phe-Gly-Pro-Met-Pro-Phe, (49) Arg-Pro-Arg-Leu
-Ser-His-Lys-Gly-Pro-Met-Pro-Cha, (50) pGlu-Arg-P
ro-Arg-Leu-Ser-His-Leu-Gly-Pro-Met-Pro-Phe, (51)
Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-NMe_Two,
(52) Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-
Mor, (53) Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Ala
-Pro-Phe (Cl), (54) Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gl
y-Gly-Met-Pro-Phe (Cl), (55) Arg-Pro-Arg-Leu-Ser-A
la-Arg-Gly-N-MeAla-Met-Pro-Phe (Cl), (56) Arg-Pro-
Arg-Leu-Ser-His-Ala-Gly-Pro-Cha-Pro-Phe (Cl), (57)
 Arg-Pro-Arg-Ala-Ser-His-Lys-Gly-Pro-Cha-Pro-Phe
(Cl), (58) Arg-Pro-Ala-Leu-Ser-His-Lys-Gly-Pro-Ch
a-Pro-Phe (Cl), (59) Arg-Arg-Gln-Arg-Pro-Arg-Leu-S
er-Ala-Arg-Gly-Pro-Met-Pro-Phe (Cl) -NH _Two, (60) Arg-
Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Cha-Pyn, (61) Arg
-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Cha-Pro-Pyn, (62)
 Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Gly-
Cha, (63) Arg-Pro-Lys (Me)_Two-Leu-Ser-Ala-Arg-Gly-Pr
o-Met-Pro-Phe, (64) Arg-Pro-Arg-Leu-Ser-Ala-Lys (M
e)_Two-Gly-Pro-Met-Pro-Phe, (65) Arg-Pro-Arg-Leu-Ser
-Dap-Arg-Gly-Pro-Cha-Pro-Phe (Cl), (66) Arg-Pro-Ar
g-Leu-Ser-Dap (Ac) -Arg-Gly-Pro-Cha-Pro-Phe (Cl),
(67) Arg-Pro-Arg-Leu-Ser-Dap (C₆) -Arg-Gly-Pro-Ch
a-Pro-Phe (Cl), and (68) Arg-Pro-Arg-Leu-Ser-Dap
(Adi) -Arg-Gly-Pro-Cha-Pro-Phe (Cl)
You.

Specific examples of the peptide represented by the above formula P1-Arg-Pro-Arg-Leu-Phe-P2-P3-Gly-Pro-P4-P5 (I) or its ester or salt thereof include Arg -Pro-Arg-Leu-Phe-Ala-Arg-Gly-Pro-Cha-Pro-Phe
(Cl), Arg-Pro-Arg-Leu-Phe-His-Lys-Gly-Pro-Cha-Pro-Phe
(Cl), Arg-Pro-Arg-Leu-Phe-His-Lys-Gly-Pro-Cha-Pro-Ph
e, Arg-Pro-Arg-Leu-Phe-His-Lys-Gly-Pro-Met-Pro-Phe
(Cl), Arg-Pro-Arg-Leu-Phe-Ala-Arg-Gly-Pro-Met-Pro-Ph
e, Arg-Pro-Arg-Leu-Phe-His-Lys-Gly-Pro-Cha-Phe (C
l), pGlu-Arg-Pro-Arg-Leu-Phe-Arg-Arg-Gly-Pro-Met-Pr
o-Phe, pGlu-Arg-Pro-Arg-Leu-Phe-His-Lys-Gly-Pro-Met-Pr
o-Phe, a peptide represented by Arg-Pro-Arg-Leu-Phe-Ala-Arg-Gly-Pro-Met-Phe, an ester thereof, or a salt thereof. Specific examples of the peptide represented by the above formula Q1-Arg-Pro-Arg-Leu-Ser-Ala-Q2-Gly-Q5-Q3-Q4 (II) or its ester or salt thereof include (i) Arg -Arg-Gln-Arg-Pro-Arg-Leu-
Ser-Ala-Arg-Gly-Pro-Met-Pro-Phe (Cl), (ii) Arg-Pro-
Arg-Leu-Ser-Ala-Arg-Gly-Pro-Met-Pro-Phe (Cl), (iii)
Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Cha-Phe (Cl),
(iv) Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Cha-Pro-P
he (Cl), (v) Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-Ala-Ar
g-Gly-Pro-Cha, (vi) Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gl
y-Pro-Cha-Pro-Phe, (vii) Arg-Arg-Gln-Arg-Pro-Arg-L
eu-Ser-Ala-Arg-Gly-Pro-Met-Pro-Phe, (viii) Arg-Arg
-Gln-Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Met, (ix)
Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro,
(x) Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Met-Pro-Ph
e, (xi) pGlu-Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-M
et-Pro-Phe, (xii) Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-
Pro-Met, (xiii) pGlu-Arg-Pro-Arg-Leu-Ser-Ala-Lys-G
ly-Pro-Met-Pro-Phe, (xiv) Arg-Pro-Arg-Leu-Ser-Ala-
Arg-Gly-Pro-Ala-Pro-Phe (Cl), (xv) Arg-Pro-Arg-Leu-
Ser-Ala-Arg-Gly-Gly-Met-Pro-Phe (Cl), (xvi) Arg-Pro
-Arg-Leu-Ser-Ala-Arg-Gly-NMe-Ala-Met-Pro-Phe (Cl),
(xvii) Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Cha-Py
n, (xviii) Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Cha
-Pro-Pyn, (xix) Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-Al
a-Arg-Gly-Gly-Cha, or (xx) Arg-Pro-Arg-Leu-Ser-
A peptide represented by Ala-Lys (Me) ₂ -Gly-Pro-Met-Pro-Phe, an ester thereof, a salt thereof, and the like.

As specific examples of the peptide represented by the above formula R1-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-R2-Pro-R3 (III), its ester or its salt, Is Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro
-Cha-Pro-Phe (Cl), Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Cha-Pro-Phe
(Cl), Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe
(Cl), pGlu-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Cha-Pr
o-Phe, pGlu-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pr
o-Phe (Cl), Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro
-Nle-Pro-Tyr, Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Nal
(2), pGlu-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pr
o-Nal (2), Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Cha
Or an ester thereof, a salt thereof, or the like. Further, the present invention provides (i) Arg-Arg-Gl
n-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met (O), (ii)
Arg-Arg-Lys (Arg-Arg) -Arg-Pro-Arg-Leu-Ser-His-Lys-
Gly-Pro-Met-Pro-Phe, (iii) Arg-Arg-Arg-Arg-Pro-Arg
-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe, (iv) Arg-Arg
-Lys-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-P
he, (v) Arg-Arg-Ala-Arg-Pro-Arg-Leu-Ser-His-Lys-Gl
y-Pro-Met-Pro-Phe, (vi) Arg-Pro-Arg-Leu-Ser-His-Ly
s-Gly-Pro-Met-Phe (Cl), (vii) pGlu-Arg-Pro-Arg-Leu-
Ser-Arg-Lys-Gly-Pro-Met-Pro-Phe, (viii) Arg-Arg-Ph
e-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Ph
e, (ix) pGlu-Arg-Pro-Arg-Leu-Ser-His-Arg-Gly-Pro-M
et-Pro-Phe, (x) pGlu-Arg-Pro-Arg-Leu-Ser-His-Lys-G
ly-Pro-Met-Phe (Cl), (xi) Arg-Pro-Arg-Leu-Ser-His-L
ys-Gly-Pro-Met-Cha, (xii) pGlu-Arg-Pro-Arg-Leu-Ser
-Leu-Lys-Gly-Pro-Met-Pro-Phe, (xiii) Arg-Pro-Arg-L
eu-Ser-His-Lys-Gly-Pro-Met-Nal (2), (xiv) pGlu-Arg-
Pro-Arg-Leu-Ser-Arg-Arg-Gly-Pro-Met-Pro-Phe, (xv)
pGlu-Arg-Pro-Arg-Leu-Ser-Phe-Lys-Gly-Pro-Met-Pro-P
he, (xvi) pGlu-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro
-Met-Cha, (xvii) pGlu-Arg-Pro-Arg-Leu-Ser-His-Lys-
Gly-Pro-Met-Nal (2), (xviii) pGlu-Arg-Pro-Arg-Leu-S
er-His-Phe-Gly-Pro-Met-Pro-Phe, (xix) pGlu-Arg-Pro
-Arg-Leu-Ser-His-Leu-Gly-Pro-Met-Pro-Phe, (xx) Arg
-Arg-Gln-Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-NMe2, (xx
i) Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Mo
r, (xxii) Arg-Pro-Arg-Leu-Ser-His-Ala-Gly-Pro-Cha-
Pro-Phe (Cl), (xxiii) Arg-Pro-Arg-Ala-Ser-His-Lys-G
ly-Pro-Cha-Pro-Phe (Cl), (xxiv) Arg-Pro-Lys (Me) ₂ -Le
u-Ser-Ala-Arg-Gly-Pro-Met-Pro-Phe, (xxv) Arg-Pro-A
rg-Leu-Ser-Dap-Arg-Gly-Pro-Cha-Pro-Phe (Cl), (xxvi)
Arg-Pro-Arg-Leu-Ser-Dap (Ac) c-Arg-Gly-Pro-Cha-Pro-
Phe (Cl), (xxvii) Arg-Pro-Arg-Leu-Ser-Dap (C6) -Arg-G
ly-Pro-Cha-Pro-Phe (Cl), (xxviii) Arg-Pro-Arg-Leu-S
er-Dap (Adi) -Arg-Gly-Pro-Cha-Pro-Phe (Cl) or (xx
ix) Arg-Pro-Ala-Leu-Ser-His-Lys-Gly-Pro-Cha-Pro-Ph
e (Cl), a peptide thereof, an ester thereof, or a salt thereof.

As a salt of the peptide of the present invention, a salt with a physiologically acceptable base (for example, an alkali metal or the like) or an acid (organic acid or inorganic acid) is used. Addition salts are preferred. Examples of such salts include salts with inorganic acids (eg, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid) and organic acids (eg, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid,
Salts with tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid) are used. The peptide of the present invention can be produced by obtaining a natural ligand by a method for purifying the peptide from human or warm-blooded animal tissues or cells, and then appropriately modifying the peptide in accordance with the peptide synthesis method described below. Alternatively, it can be produced according to a peptide synthesis method described later without using a natural ligand as a raw material. When a natural ligand is produced from human or warm-blooded animal tissue or cells, the human or warm-blooded animal tissue or cells are homogenized, and then extracted with an acid or the like. Dialysis,
Purification and isolation can be achieved by combining chromatography such as gel filtration, reverse phase chromatography, ion exchange chromatography, and affinity chromatography. The method for obtaining the natural ligand is as follows:
For example, WO 99/33976 (Japanese Patent Application No. 10-22)
No. 0853). The peptide of the present invention can be produced according to a peptide synthesis method known per se. As a method for synthesizing a peptide, for example, any of solid phase synthesis and liquid phase synthesis may be used. That is, the target peptide can be produced by condensing a partial peptide or amino acid capable of constituting the peptide of the present invention with the remaining portion and, when the product has a protecting group, removing the protecting group. Known methods for condensation and elimination of protecting groups include, for example, the methods described in (1) to (4) below. M. Bodanszky and MA Ondetti, Peptide Synthesis, Interscience Publisher
s, New York (1966) Schroeder and Luebke, The Peptide,
Academic Press, New York (1965) Nobuo Izumiya et al., Fundamentals and experiments of peptide synthesis, Maruzen Co., Ltd.
(1975) Haruaki Yajima and Shunpei Sakakibara, Laboratory of Biochemistry 1, Protein Chemistry IV, 205, (1977) Supervised by Haruaki Yajima, Development of Continuing Drugs Volume 14 Peptide Synthesis Hirokawa Shoten

After the reaction, a usual purification method, for example,
The peptide of the present invention can be purified and isolated by a combination of solvent extraction, distillation, column chromatography, liquid chromatography, recrystallization and the like. When the peptide obtained by the above method is a free form, it can be converted to an appropriate salt by a known method, and when it is obtained as a salt, it can be converted to a free form by a known method. . Regarding condensation of the protected amino acid or peptide, various activating reagents that can be used for peptide synthesis can be used, and in particular, trisphosphoniums, tetramethyluroniums, carbodiimides and the like are preferable.
Trisphosphoniums include benzotriazole-
1-yloxytrispirolidinophosphonium hexafluorophosphate (PyBOP), bromotrispirolidinophosphonium hexafluorophosphate
(PyBroP), as tetramethyluroniums, 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate, 2- (5-norbornene-2 , 3-
Dicarboximide) -1,1,3,3-tetramethyluronium tetrafluoroborate, O- (N-succimidyl) -1,1,
3,3-tetramethyluronium tetrafluoroborate,
Examples of the carbodiimides include DCC, N, N'-diisopropylcarbodiimide, N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide, and the like. For the condensation by these, addition of a racemization inhibitor (eg, HONB, HOBt, HOOBt, etc.) is preferred. The solvent used for the condensation can be appropriately selected from solvents known to be usable for the peptide condensation reaction. For example, anhydrous or water-containing acid amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, halogenated hydrocarbons such as methylene chloride and chloroform, alcohols such as trifluoroethanol, and dimethyl Sulfoxides such as sulfoxide, tertiary amines such as pyridine, ethers such as dioxane and tetrahydrofuran, nitriles such as acetonitrile and propionitrile, esters such as methyl acetate and ethyl acetate, and appropriate mixtures thereof are used. Can be The reaction temperature is appropriately selected from a range known to be usable for the peptide bond formation reaction, and is usually about -20 ° C to 5 ° C.
It is appropriately selected from the range of 0 ° C. The activated amino acid derivative is usually used in a 1.5 to 4-fold excess. In the case of solid phase synthesis, as a result of a test using the ninhydrin reaction, if the condensation is insufficient, sufficient condensation can be performed by repeating the condensation reaction without removing the protecting group. When a sufficient condensation cannot be obtained by repeating the reaction, the unreacted amino acid can be acetylated using acetic anhydride or acetylimidazole so as not to affect the subsequent reaction. Examples of the protecting group for the amino group of the starting amino acid include Z, Boc, tert-pentyloxycarbonyl, isobornyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
Cl-Z, Br-Z, adamantyloxycarbonyl, trifluoroacetyl, phthaloyl, formyl, 2-nitrophenylsulfenyl, diphenylphosphinothioyl, Fm
oc and the like. Examples of the carboxyl-protecting group include the above-mentioned C _1-6 alkyl group as R, C _3-8
Cycloalkyl, C _7-14 aralkyl, allyl,
2-adamantyl, 4-nitrobenzyl, 4-methoxybenzyl, 4-chlorobenzyl, phenacyl group and benzyloxycarbonyl hydrazide, tert-butoxycarbonyl hydrazide, trityl hydrazide and the like. The hydroxyl groups of serine and threonine can be protected, for example, by esterification or etherification. Groups suitable for this esterification include, for example, groups derived from organic acids such as lower (C _2-4 ) alkanoyl groups such as acetyl group and aroyl groups such as benzoyl group. Examples of groups suitable for etherification include a benzyl group, a tetrahydropyranyl group, a tertiary butyl group, and a trityl group (Trt).
Examples of the protecting group for the phenolic hydroxyl group of tyrosine include Bzl, 2,6-dichlorobenzyl, 2-nitrobenzyl, Br-Z, tert-butyl and the like. The protecting groups for histidine imidazolyl include Tos, 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), DN
P, Bom, Bum, Boc, Trt, Fmoc and the like. Protecting groups for the guanidino group of arginine include Tos, Z, 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), p-
Methoxybenzenesulfonyl (MBS), 2,2,5,7,8-pentamethylchroman-6-sulfonyl (Pmc), mesitylene-2
-Sulfonyl (Mts), 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf), Boc, Z, NO _{2 and the} like.

As protecting groups for the side chain amino group of lysine, Z,
Cl-Z, trifluoroacetyl, Boc, Fmoc, Trt, Mtr,
4,4-dimethyl-2,6-dioxocyclohexylideneyl (Dde) and the like. Formyl (For), Z, Boc, Mts, Mt
r and the like. Asparagine and glutamine protecting groups include Trt, xanthyl (Xan), 4,4'-dimethoxybenzhydryl (Mbh), 2,4,6-trimethoxybenzyl (Tmo
b) and the like. Examples of the activated carboxyl group of the raw material include the corresponding acid anhydride, azide, active ester [alcohol (eg, pentachlorophenol, 2,4,5-trichlorophenol, 2,4-dinitrophenol, cyanophenol) Methyl alcohol, para-nitrophenol, HONB, N-hydroxysuccinimide, 1-hydroxybenzotriazole, ester with (HOBt)]
And the like. The activated amino group of the raw material includes, for example, the corresponding phosphite. As a method of removing (eliminating) the protecting group, for example, catalytic reduction in a hydrogen stream in the presence of a catalyst such as Pd black or Pd carbon, hydrogen fluoride anhydride, methanesulfonic acid, trifluoromethanesulfonic acid Acid treatment with trifluoroacetic acid, trimesylsilane bromide (TMSBr), trimethylsilyl trifluoromethanesulfonate, tetrafluoroboric acid, tris (trifluoro) boron, boron tribromide or a mixture thereof, diisopropylethylamine, triethylamine , Piperidine, piperazine, etc., and reduction with sodium in liquid ammonia. The elimination reaction by the acid treatment is generally performed at a temperature of -20 ° C to 40 ° C. In the acid treatment, a cation scavenger such as anisole, phenol, thioanisole, metacresol, paracresol, dimethyl sulfide, It is effective to add 1,4-butanedithiol, 1,2-ethanedithiol and the like.
Further, the 2,4-dinitrophenyl group used as an imidazole protecting group of histidine is removed by thiophenol treatment, and the formyl group used as an indole protecting group of tryptophan is 1,2-ethanedithiol, 1,1,
In addition to deprotection by acid treatment in the presence of 4-butanedithiol or the like, it is also removed by alkali treatment with dilute sodium hydroxide, dilute ammonia or the like. The protection and protection of the functional group that should not be involved in the reaction of the raw materials, the elimination of the protective group, the activation of the functional group involved in the reaction, and the like can be appropriately selected from known groups or known means. As a method for obtaining the amide form of the peptide, solid phase synthesis using a resin for amide form synthesis or after amidating the α-carboxyl group of the carboxyl terminal amino acid, the peptide chain on the amino group side to the desired chain length After the elongation, a peptide was prepared by removing only the protecting group of the N-terminal α-amino group of the peptide chain, and a peptide (or amino acid) was obtained by removing only the protecting group of the C-terminal carboxyl group. The condensation is carried out in a mixed solvent as described above. Details of the condensation reaction are the same as described above. After purifying the protected peptide obtained by the condensation, all the protecting groups are removed by the above-mentioned method to obtain a desired crude polypeptide.
This crude peptide is purified by using various known purification means, and the main fraction is freeze-dried to obtain an amide of the desired peptide. To obtain an ester of the peptide, the α-carboxyl group of the carboxy terminal amino acid is condensed with a desired alcohol to form an amino acid ester, and then an ester of the desired peptide can be obtained in the same manner as the amide of the peptide. The peptide of the present invention
Furthermore, it may be a fusion protein with a protein whose function or property is well known.

The peptide of the present invention can be used to search for physiological functions possessed by the peptide of the present invention, to develop a receptor binding assay system using a recombinant receptor protein expression system and to screen drug candidate compounds, It can be used for the development of medicines such as circulatory function regulators, heart function regulators, immune function regulators, gastrointestinal function regulators, metabolic function regulators and genital function regulators. In particular, by a receptor binding assay system using a recombinant G protein-coupled receptor protein expression system described below, a G protein-coupled receptor agonist or antagonist specific to a warm-blooded animal such as human can be screened, The agonist or antagonist can be used as an agent for preventing or treating various diseases. Further, with respect to the above, the peptide of the present invention is a G protein-coupled receptor protein (eg, APJ) expressed in the central nervous system, circulatory system, heart, immune system, digestive system, metabolic system, reproductive system and the like. Since it is recognized as a ligand, it is useful as a safe and low toxic drug. Since the peptide of the present invention is involved in central nervous system function control, circulatory function control, heart function control, immune function control, digestive function control, metabolic function control or genital function control, etc. For example, senile dementia, cerebrovascular dementia, degenerative degenerative diseases caused by phylogenetic transformation (eg, Alzheimer's disease, Parkinson's disease, Pick's disease, Huntington's disease, etc.), infectious diseases (eg, Creutzfeldt-Jakob disease) Late viral infections, etc.)
Dementia, endocrine, metabolic, or toxic diseases (eg:
Dementia due to hypothyroidism, vitamin B12 deficiency, alcohol intoxication, intoxication with various drugs, metals and organic compounds, dementia due to neoplastic disease (eg, brain tumor, etc.), traumatic disease (eg, chronic hard disease) Dementia such as dementia caused by submembrane hematoma), depression, hyperactive child (microbrain disorder) syndrome, consciousness disorder, anxiety disorder, schizophrenia, phobia, impaired growth hormone secretion (eg, giantosis, acromegaly) Bulimia, bulimia, bulimia, hypercholesterolemia, hyperglyceridemia, hyperlipidemia, hyperprolactinemia, diabetes (eg, diabetic complications, diabetic nephropathy, diabetic neuropathy, Diabetic retinopathy, etc.), cancer (eg, breast cancer, lymphocytic leukemia, lung cancer, bladder cancer, ovarian cancer, prostate cancer, etc.), pancreatitis, renal disease (eg, chronic renal failure, nephritis, etc.), Turner syndrome, neurosis , Rheumatoid arthritis, spine Injury, transient ischemic attack, amyotrophic lateral sclerosis, acute myocardial infarction, spinocerebellar degeneration, fracture, wound, atopic dermatitis, osteoporosis, asthma, epilepsy, infertility, arteriosclerosis, emphysema, It can be used as an agent for treating or preventing diseases such as pulmonary edema or lactation deficiency. Further, it can be used as a postoperative nutritional condition improving agent, a vasopressor, and the like.

In addition, HIV infection, AIDS (AIDS)
(Acquired Immune Deficiency Syndrome): It can be used as a therapeutic or prophylactic agent for acquired immunodeficiency syndrome. When the peptide of the present invention is used as the above-mentioned medicine, it can be carried out according to a conventional method. For example, a sugar-coated or enteric-coated tablet as required, a capsule, a elixir, orally as a microcapsule, or a sterile solution with water or another pharmaceutically acceptable liquid, Alternatively, it can be used parenterally in the form of injections such as suspensions. For example, a physiologically acceptable carrier, flavoring agent, excipient, the compound or a salt thereof,
It can be prepared by admixing it with a vehicle, preservative, stabilizer, binder and the like in a unit dosage form required for a generally accepted pharmaceutical practice. The amount of the active ingredient in these preparations is such that a proper dosage in the specified range can be obtained. Examples of additives that can be incorporated into tablets, capsules and the like include binders such as gelatin, corn starch, tragacanth gum, gum arabic, excipients such as crystalline cellulose, corn starch, gelatin, alginic acid and the like. Swelling agents, lubricants such as magnesium stearate, sweeteners such as sucrose, lactose or saccharin, flavoring agents such as peppermint, reddish oil or cherry are used.
When the preparation unit form is a capsule, a liquid carrier such as oil and fat can be further contained in the above-mentioned type of material. Sterile compositions for injection can be formulated according to normal pharmaceutical practice such as dissolving or suspending the active substance in vehicles such as water for injection, naturally occurring vegetable oils such as sesame oil, coconut oil and the like. . Aqueous liquids for injection include, for example, physiological saline, isotonic solutions containing glucose and other adjuvants (eg, D-sorbitol, D-sorbitol).
Mannitol, sodium chloride, etc.)
Suitable solubilizers, such as alcohols (eg, ethanol), polyalcohols (eg, propylene glycol, polyethylene glycol), non-ionic surfactants (eg, polysorbate 80 (TM), HCO-5)
0) and the like. The oily liquid includes sesame oil, soybean oil and the like, and may be used in combination with benzyl benzoate, benzyl alcohol and the like as a solubilizing agent. Also,
Buffers (eg, phosphate buffer, sodium acetate buffer), soothing agents (eg, benzalkonium chloride, procaine hydrochloride, etc.), stabilizers (eg, human serum albumin, polyethylene glycol, etc.), preservatives ( For example,
Benzyl alcohol, phenol, etc.), antioxidants and the like. The prepared injection is usually filled in a suitable ampoule. Since the thus obtained preparation is safe and has low toxicity, it is useful for mammals (for example, human, mouse, rat, guinea pig, rabbit, sheep, pig, cow, cat, dog, monkey, chimpanzee, etc.). Can be administered. The dose of the peptide of the present invention varies depending on symptoms and the like, but in the case of oral administration, generally, in an adult HIV-infected patient (with a body weight of 60 kg), about 0.1 to 100 mg per day is preferable. Is about 1.0 to 50 mg, more preferably about 1.0 to 20 mg. When administered parenterally, 1
The dose may vary depending on the administration target, target organ, symptoms, administration method, etc.
For administration to an infectious disease patient (assuming a body weight of 60 kg), about 0.01 to 30 mg per day, preferably about 0.1 to 20 mg, more preferably about 0.1 to 20 mg per day.
It is convenient to administer from about 10 mg to about 10 mg by intravenous injection. In the case of other animals, the dose can be administered in terms of 60 kg.

Examples of the G protein-coupled receptor protein for the peptide of the present invention include humans and warm-blooded animals (eg, warm-blooded mammals (eg, rabbits, sheep, goats, rats, mice, guinea pigs, cows, horses, pigs). ), Birds (eg, chickens, pigeons, ducks, geese, quails), etc.) (eg, pituitary, pancreas, brain, kidney, liver, gonads, thyroid, gallbladder, bone marrow, adrenal glands, skin, muscle, lungs) G protein-coupled receptor protein derived from, for example, a gastrointestinal tract, blood vessel, or heart) or a cell, for example, having an amino acid sequence identical or substantially identical to the amino acid sequence represented by SEQ ID NO: 19. If it is, any thing may be used. That is, the G protein-coupled receptor protein includes, in addition to the protein containing the amino acid sequence represented by SEQ ID NO: 19 in the present specification, etc., the amino acid sequence represented by SEQ ID NO: 19 in the present specification; 99.
A protein containing an amino acid sequence having 9% homology and having substantially the same activity as the protein containing the amino acid sequence represented by SEQ ID NO: 19 in the present specification can be mentioned. The activities exhibited by these proteins include, for example, ligand binding activity and signal transduction activity. “Substantially the same” means that the ligand binding activity and the like are the same in nature. Therefore, the quantitative factors such as the strength of the ligand binding activity and the molecular weight of the receptor protein may be different. Further, G protein-coupled receptor proteins include those in which the N-terminal Met is protected with a protecting group (for example, a C _1-6 acyl group such as a C _2-6 alkanoyl group such as formyl and acetyl);
ln is cleaved in vivo at the N-terminal side, the Gln is pyroglutamine-oxidized, and the side chain of an amino acid residue in the molecule has an appropriate protecting group (for example, Cyl group such as formyl group or acetyl group).
_1-6 acyl group) or complex proteins such as so-called glycoproteins to which sugar chains are bound. Examples of the salt of the G protein-coupled receptor protein include those similar to the salts of the above-described peptide.
The G protein-coupled receptor protein or a salt thereof or a partial peptide thereof can be produced from a human or warm-blooded animal tissue or cell by a protein purification method known per se, or according to the aforementioned peptide synthesis method. It can also be manufactured. As the partial peptide of the G protein-coupled receptor protein, for example, a site of the G protein-coupled receptor protein molecule that is exposed outside the cell membrane is used. That is, it is a peptide containing a portion analyzed as an extracellular region (hydrophilic site) in a hydrophobic plot analysis of a G protein-coupled receptor protein. Further, a peptide partially containing a hydrophobic (Hydrophobic) site can also be used. A peptide containing individual domains may be used, but a peptide containing a plurality of domains at the same time may be used.

As the salt of the partial peptide of the G protein-coupled receptor protein, those similar to the salts of the above-mentioned peptides can be used. The DNA encoding the G protein-coupled receptor protein includes SEQ ID NO:
Any nucleotide may be used as long as it contains a nucleotide sequence encoding a G protein-coupled receptor protein containing the same or substantially the same amino acid sequence as the amino acid sequence of No. 19. Genomic DNA, genomic DNA
Any of a library, a cDNA derived from a tissue / cell, a cDNA library derived from a tissue / cell, and a synthetic DNA may be used. The vector used for the library may be any of bacteriophage, plasmid, cosmid, phagemid and the like. Alternatively, it can also be directly amplified by a known RT-PCR method using an RNA fraction prepared from tissues or cells. Specifically, DN encoding a G protein-coupled receptor protein containing the amino acid sequence represented by SEQ ID NO: 19 in the present specification
As A, a DNA having the base sequence represented by SEQ ID NO: 20 in the present specification is used.

The use of the peptide of the present invention or a salt thereof (hereinafter, sometimes abbreviated as the peptide of the present invention) is specifically described below. (1) Agent for Prevention / Treatment of Ligand Peptide Deficiency Depending on the action of the peptide of the present invention on G protein-coupled receptor protein (APJ), the peptide of the present invention can be used as a ligand peptide or G protein-coupled receptor protein (APJ). ) It can also be used as a prophylactic / therapeutic agent for deficiency. For example, in vivo, since the G protein-coupled receptor protein (APJ) is reduced, physiological effects of ligands (control of central nervous function, control of circulatory function, control of heart function, control of immune function,
Digestive function, metabolic function or genital function).
By administering the peptide or the like of the present invention to the patient,
The amount of the ligand peptide in the living body of the patient can be increased, and the action of the ligand peptide can be sufficiently exerted. Therefore, the peptide or the like of the present invention can be used as a safe and low-toxicity preventive or therapeutic agent for ligand peptide deficiency. (2) Method for quantifying G protein-coupled receptor protein (APJ) for ligand peptide The peptide of the present invention binds to G protein-coupled receptor protein (APJ) or a salt thereof, a partial peptide of the receptor protein or a salt thereof. Because it has the nature
G protein-coupled receptor protein (AP) in vivo
The concentration of J) or a salt thereof, a partial peptide of the receptor protein, an amide thereof, an ester thereof, or a salt thereof can be quantified with high sensitivity. The G
As the partial peptide of the protein-coupled receptor protein (APJ), for example, a site of the G protein-coupled receptor protein (APJ) molecule that is exposed outside the cell membrane is used. That is, it is a peptide containing a portion analyzed as an extracellular region (hydrophilic site) in a hydrophobic plot analysis of a G protein-coupled receptor protein (APJ). Hydrophobic (Hydropho
bic) A peptide partially containing a site can also be used. A peptide containing individual domains may be used, but a peptide containing a plurality of domains at the same time may be used. The amide and ester of the partial peptide of the G protein-coupled receptor protein (APJ) can be obtained in the same manner as the amide or ester of the peptide of the present invention described above. In addition, G protein-coupled receptor protein (AP
As the salt of the partial peptide of J), those similar to the salts of the peptide of the present invention described above are used. This quantification method
For example, it can be used in combination with a competition method. That is, a G protein-coupled receptor protein (APJ) or a salt thereof, or a partial peptide of the G protein-coupled receptor protein (APJ) or an amide or ester thereof in the sample is brought into contact with the sample by contacting the sample with the peptide of the present invention. Alternatively, the concentration of the salt can be measured. Specifically, for example, it can be used according to a method known per se described below or the like or a method analogous thereto. Edited by Hiro Irie "Radio Immunoassay" (Kodansha, Showa 4)
(Published in 1995) Hiroshi Irie, "Continuing Radio Immunoassay" (Kodansha, published in 1979)

(3) Method for screening a compound that alters the binding between the G protein-coupled receptor protein (APJ) and the peptide of the present invention, etc. G protein-coupled receptor protein (APJ) or a salt thereof, or its partial peptide or By using an amide, ester or a salt thereof, or constructing an expression system of a recombinant receptor protein (APJ) and using a receptor binding assay system using the expression system, the peptide of the present invention and the G protein can be obtained. Coupled receptor protein (APJ)
(Eg, peptides, proteins, non-peptidic compounds, synthetic compounds, fermentation products, etc.) or salts thereof can be screened.
Such compounds include G protein-coupled receptors (A
Cell stimulating activity (eg, arachidonic acid release, acetylcholine release, intracellular Ca ²⁺ release, intracellular c
AMP production, intracellular cGMP production, inositol phosphate production, cell membrane potential fluctuation, intracellular protein phosphorylation, c-
Compounds having an activity of promoting or suppressing fos activation, lowering of pH, etc. (ie, G protein-coupled receptor agonist) and compounds having no such cell stimulating activity (ie, G protein-coupled receptor antagonist) Is included. The term "altering binding" includes both cases of inhibiting the binding to the peptide or the like of the present invention and promoting the binding to the peptide or the like of the present invention. That is, the present invention relates to (i) a case where the peptide or the like of the present invention is brought into contact with a G protein-coupled receptor protein (APJ) or a salt thereof, or a partial peptide of the receptor protein or a salt thereof; A comparison is made between the case where the peptide of the present invention and a test compound are brought into contact with a protein-coupled receptor protein (APJ) or a salt thereof, or a partial peptide of the receptor protein or an amide, ester or a salt thereof. A method for screening a compound or a salt thereof that alters the binding property between the peptide of the present invention and the above-mentioned G protein-coupled receptor protein (APJ). In the screening method of the present invention, (i) the case where the peptide or the like of the present invention is brought into contact with the above-mentioned G protein-coupled receptor protein (APJ) or a partial peptide of the receptor protein; When the peptide or the like of the present invention and a test compound are brought into contact with the receptor protein of the present invention (APJ) or a partial peptide of the receptor protein, for example, the G protein-coupled receptor protein (APJ) or the partial peptide of the receptor protein The binding amount of the peptide of the invention, the cell stimulating activity and the like are measured and compared.

In the screening method of the present invention, specifically, the labeled peptide of the present invention can be prepared by converting the above-mentioned G protein-coupled receptor protein (APJ) or a salt thereof or a partial peptide of the G protein-coupled receptor protein (APJ) Or, when it is brought into contact with an amide, an ester or a salt thereof, and the labeled peptide or the like of the present invention and a test compound, the G protein-coupled receptor protein (APJ) or a salt thereof or a portion of the G protein-coupled receptor protein (APJ) The G protein-coupled receptor protein (APJ) such as a labeled peptide of the present invention or a salt thereof, or the partial peptide or an amide, ester or a salt thereof when contacted with a peptide or an amide, ester or a salt thereof. Measure and compare the amount of binding to A method for screening a compound or a salt thereof that alters the binding property between the peptide or the like of the present invention and a G protein-coupled receptor protein (APJ); (APJ) -containing cells or a membrane fraction of the cells, and a cell containing the G protein-coupled receptor protein (APJ) or a membrane of the cells containing the labeled peptide or the like of the present invention and a test compound. Measuring the amount of binding of the labeled peptide or the like of the present invention to the cell or the membrane fraction when contacted with the fraction, and comparing the peptide or the like with the G protein-coupled receptor protein. (A) A method for screening a compound or a salt thereof that alters the binding to (APJ); A G protein-coupled receptor protein (APJ) expressed on a cell membrane by culturing a transformant containing a DNA encoding a type receptor protein (APJ); The test compound was labeled when it was brought into contact with the G protein-coupled receptor protein (APJ) expressed on the cell membrane by culturing a transformant containing the DNA encoding the G protein-coupled receptor protein (APJ). The amount of binding of the peptide of the present invention to the G protein-coupled receptor protein is measured and compared, and the peptide or the like of the present invention and the G protein-coupled receptor protein (A
A method for screening a compound or a salt thereof that alters the binding to PJ), comprising a compound that activates a G protein-coupled receptor (APJ) (for example, the peptide of the present invention) and a G protein-coupled receptor protein (APJ) G protein-coupled receptor in the case of contacting with cells and in the case where a compound activating G protein-coupled receptor (APJ) and a test compound are contacted with cells containing G protein-coupled receptor protein (APJ) (APJ) -mediated cell stimulating activity (eg, arachidonic acid release, acetylcholine release, intracellular Ca ²⁺ release, intracellular cAMP production, intracellular cGMP production, inositol phosphate production, cell membrane potential fluctuation, intracellular protein phosphorus Oxidation, activation of c-fos,
or a compound that alters the binding between the peptide or the like of the present invention and a G protein-coupled receptor protein (APJ), which is characterized by measuring and comparing the activity of promoting or suppressing pH reduction. A method for screening a salt, and a method for activating a compound that activates a G protein-coupled receptor (APJ) (for example, the peptide of the present invention) using a transformant containing a DNA encoding a G protein-coupled receptor protein (APJ) The culture was brought into contact with a G protein-coupled receptor protein (APJ) expressed on the cell membrane, and the G protein-coupled receptor (AP
A compound which activates J) and a test compound which is a DNA encoding a G protein-coupled receptor protein (APJ)
G protein-coupled receptor protein (APJ) expressed on the cell membrane by culturing a transformant containing
Cell-stimulating activity (eg, arachidonic acid release, acetylcholine release, intracellular Ca ²⁺ release, intracellular cAMP production, intracellular cGMP production, inositol phosphate when contacted with Production, cell membrane potential fluctuation, intracellular protein phosphorylation,
binding to the G protein-coupled receptor protein (APJ) and the peptide or the like of the present invention, wherein the activity of promoting or suppressing c-fos activation, pH reduction, etc.) is measured and compared. And a method of screening for a compound or a salt thereof that changes the sex.

A specific description of the screening method of the present invention will be given below. First, as the G protein-coupled receptor protein (APJ) used in the screening method of the present invention, the above-mentioned G protein-coupled receptor protein or G protein
Any protein may be used as long as it contains a partial peptide of the protein-coupled receptor protein, but a membrane fraction of an organ of a human or a warm-blooded animal is suitable. However, since it is particularly difficult to obtain human-derived organs, G-protein-coupled receptor protein (AP
J) is suitable. In the screening method of the present invention, when a cell containing a G protein-coupled receptor protein or a cell membrane fraction thereof is used, the preparation method described later may be followed. When cells containing a G protein-coupled receptor protein are used, the cells may be immobilized with glutaraldehyde, formalin, or the like. The immobilization method can be performed according to a method known per se. Cells containing a G protein-coupled receptor protein include G
A host cell expressing a protein-coupled receptor protein is used. Examples of the host include Escherichia, Bacillus, yeast, insects or insect cells, and animal cells. Examples of the genus Escherichia include Escherichia coli K12 DH1 [Processings of the National Academy of
Sciences of the USA (Proc. Nat)
l. Acad. Sci. USA), 60, 160 (196)
8)], JM103 [Nucleic Acids Research, (Nucleic Acids Research), 9, 309 (19)
81)], JA221 [Journal of Molecular Biolog
y)], 120, 517 (1978)], HB101
[Journal of Molecular Biology, 4
1, 459 (1969)], C600 [Genetics, 39, 440 (1954)] and the like. Bacillus spp.
Bacillus subtilis MI114 [Gene,
24, 255 (1983)], 207-21 [Journal of Biochemis
try), 95, 87 (1984)].
Examples of yeast include Saccharomyces cerevisiae AH22, AH22
^{R -, NA87-11A, DKD-5D} , 20B-12
Are used. As insects, for example, silkworm larvae are used [Maeda et al., Nature, 3
15, 592 (1985)]. As insect cells, for example, when the virus is AcNPV, a cell line derived from the larva of night-moth (Spodoptera frugiperda cell; Sf cell);
MG1 cells from Trichoplusia ni midgut, Trichoplusi
High Five ^TM cells derived from a ni eggs, Mamestra brassicae
Derived cells or cells derived from Estigmena acrea are used. When the virus is BmNPV, a silkworm-derived cell line (Bombyx mori N; BmN cell) or the like is used. As the Sf cells, for example, Sf9 cells (ATCC C
RL1711), Sf21 cells (Vaughn, JL et al., In Vitro, 13, 213-217 (1977)) and the like. Examples of animal cells include monkey COS-7 cells, Vero cells, Chinese hamster cells CHO, DHFR gene-deficient Chinese hamster cells CHO (dhfr ^- CHO cells), mouse L cells, mouse 3T3 cells, mouse myeloma cells, human HEK293 cells, Human FL cells, 29
3 cells, C127 cells, BALB3T3 cells, Sp-2
/ O cells are used. The membrane fraction refers to a fraction abundant in cell membrane obtained by disrupting cells and then obtained by a method known per se. As a method for disrupting cells,
Examples of the method include crushing cells with a Potter-Elvehjem homogenizer, crushing with a Waring blender or a polytron (manufactured by Kinematica), crushing with ultrasonic waves, crushing by ejecting cells from a thin nozzle while applying pressure with a French press, and the like. . For fractionation of cell membranes, fractionation by centrifugal force, such as fractionation centrifugation and density gradient centrifugation, is mainly used. For example, the cell lysate is centrifuged at a low speed (500 rpm to 3000 rpm) for a short time (typically, about 1 minute to 10 minutes), and the supernatant is further centrifuged at a high speed (15,000 rpm).
(rpm to 30,000 rpm) for 30 minutes to 2 hours, and the resulting precipitate is used as a membrane fraction. The membrane fraction is rich in the expressed G protein-coupled receptor protein and many membrane components such as cell-derived phospholipids and membrane proteins. The amount of the G protein-coupled receptor protein in the cells or the membrane fraction containing the G protein-coupled receptor protein is preferably 10 ³ to 10 ⁸ molecules per cell, preferably 10 ⁵ to 10 ^7.
Preferably it is a molecule. The higher the expression level, the higher the ligand binding activity (specific activity) per membrane fraction,
Not only can a highly sensitive screening system be constructed, but also a large number of samples can be measured in the same lot.

In order to screen for a compound that alters the binding property between the peptide or the like of the present invention and a G protein-coupled receptor, the above-mentioned steps (1) to (3) are carried out by selecting an appropriate G protein-coupled receptor fraction and the labeled G protein-coupled receptor. Are used. As the G protein-coupled receptor fraction, a natural G protein-coupled receptor fraction or a recombinant G protein-coupled receptor fraction having an activity equivalent thereto is desirable. Here, the equivalent activity is
It shows equivalent ligand binding activity and the like. As the labeled ligand, a labeled ligand, a labeled ligand analog compound, or the like is used. For example, [ ³ H],
Ligands labeled with [ ¹²⁵ I], [ ¹⁴ C], [ ³⁵ S] and the like can be used. Specifically, to screen for a compound that alters the binding between the peptide or the like of the present invention and a G protein-coupled receptor protein,
First, a receptor preparation is prepared by suspending a cell or a membrane fraction of the cell containing the G protein-coupled receptor protein (APJ) in a buffer suitable for screening. The buffer may have a pH of 4 to 10 (preferably p
Any buffer may be used as long as it does not inhibit the binding between the ligand and the receptor, such as a phosphate buffer of H6 to 8) and a Tris-HCl buffer. Further, in order to reduce non-specific binding, CHAPS, Tween-80 ^™
Surfactants such as (Kao-Atlas), digitonin and deoxycholate can also be added to the buffer.
Furthermore, PMSF, leupeptin,
Protease inhibitors such as E-64 (manufactured by Peptide Research Laboratories) and pepstatin can also be added. 0.01ml
Add a fixed amount (5000 c) to 10 ml of the receptor solution.
pm to 500,000 cpm), and a test compound of 10 ^-4 to 10 ^-1 μM is coexistent with the peptide. A reaction tube containing a large excess of the unlabeled peptide of the present invention or the like is also prepared to determine the non-specific binding amount (NSB). The reaction is carried out at 0 ° C to 50 ° C, preferably 4 ° C.
C. to 37.degree. C. for 20 minutes to 24 hours, preferably 30 minutes to 3 hours. After the reaction, the mixture is filtered with a glass fiber filter paper or the like,
After washing with an appropriate amount of the same buffer, the radioactivity remaining on the glass fiber filter paper is measured with a liquid scintillation counter or a γ-counter. When the count (B ₀ −NSB) obtained by subtracting the non-specific binding amount (NSB) from the count (B ₀ ) in the case where there is no antagonistic substance is 100%, the specific binding amount (B-NSB) is, for example, 50%. % Of the test compound can be selected as a candidate substance capable of competitive inhibition. In order to carry out a method of screening for a compound that alters the binding property between the peptide or the like of the present invention and a G protein-coupled receptor protein (APJ), a cell stimulating activity through the G protein-coupled receptor protein (for example, arachidonic acid) Release, acetylcholine release, intracellular C
a ²⁺ release, intracellular cAMP production, intracellular cGMP production,
Inositol phosphate production, cell membrane potential fluctuation, intracellular protein phosphorylation, activation of c-fos, activity to promote or suppress pH reduction, etc.) using a known method or a commercially available measurement kit. Can be measured. Specifically, first, cells containing a G protein-coupled receptor protein are cultured in a multiwell plate or the like. Before performing screening, the cells were exchanged with a fresh medium or an appropriate buffer that is not toxic to cells, and a test compound was added and incubated for a certain period of time. The product is quantified according to the respective method. Substance used as an indicator of cell stimulating activity (eg, arachidonic acid)
If the production of is difficult by the use of a degrading enzyme contained in the cell, the assay may be performed by adding an inhibitor against the degrading enzyme. In addition, the activity such as cAMP production suppression can be detected as a production suppression effect on cells whose basic production amount has been increased by forskolin or the like. In order to perform screening by measuring cell stimulating activity, cells expressing an appropriate G protein-coupled receptor protein are required. Cells expressing the G protein-coupled receptor protein of the present invention include the aforementioned recombinant G protein-coupled receptor protein (APJ).
An expression cell line is desirable. Test compounds include, for example, peptides, proteins, non-peptide compounds, synthetic compounds, fermentation products, cell extracts, plant extracts, animal tissue extracts, and the like, and these compounds may be novel compounds. Alternatively, a known compound may be used. The peptide or the like of the present invention and a G protein-coupled receptor protein (AP
A kit for screening a compound or a salt thereof that alters the binding property to J) comprises a G protein-coupled receptor protein or a salt thereof, a partial peptide of the G protein-coupled receptor protein or an amide or an ester thereof, or a G protein A cell containing a coupled receptor protein or a membrane fraction of a cell containing a G protein-coupled receptor protein, and the peptide of the present invention.

Examples of the screening kit of the present invention include the following. 1. Screening reagent Measurement buffer and washing buffer Hanks' Balanced Salt Solution (manufactured by Gibco)
One containing 05% bovine serum albumin (manufactured by Sigma). The solution may be sterilized by filtration through a 0.45 μm filter and stored at 4 ° C., or may be prepared at use. G protein-coupled receptor (APJ) standard CHO cells expressing the G protein-coupled receptor protein (APJ) were subcultured on a 12-well plate at 5 × 10 ⁵ cells / well at 37 ° C., 5% CO _2. , Cultured for 2 days at 95% air. The peptide of the present invention labeled with [ ³ H], [ ¹²⁵ I], [ ¹⁴ C], [ ³⁵ S], etc., dissolved in an appropriate solvent or buffer at 4 ° C. Store at −20 ° C. and dilute to 1 μM with measuring buffer before use. Standard solution of the peptide etc. of the present invention The peptide etc. of the present invention is dissolved to a concentration of 1 mM in PBS containing 0.1% bovine serum albumin (Sigma),
Store at -20 ° C. 2. Assay method G-protein-coupled receptor protein (APJ) -expressed cells cultured on a 12-well tissue culture plate were washed twice with 1 ml of assay buffer, and then 490 μl of assay buffer was added to each well. Add. After adding 5 μl of a 10 ⁻³ to 10 ⁻¹⁰ M test compound solution, 5 μl of the labeled peptide of the present invention and the like are added, and the mixture is reacted at room temperature for 1 hour. To determine the amount of non-specific binding, 5 μl of 10 ⁻³ M ligand is added instead of the test compound. Remove the reaction solution and wash 3 times with 1 ml of washing buffer. 0.2 N N
Dissolve in aOH-1% SDS and mix with 4 ml of liquid scintillator A (Wako Pure Chemical Industries). Liquid scintillation counter (Beckman)
Radioactivity was measured using Percent Maximum Binding
(PMB) is obtained by the following equation (Equation 1). [Equation 1] PMB = [(B−NSB) / (B ₀ −NSB)] × 10
0 PMB: Percent Maximum Binding B: Value when a sample is added NSB: Non-specific Binding (Non-specific binding amount) B ₀ : Maximum binding amount Compound or compound obtained by using the screening method or the screening kit of the present invention or The salt is a compound that changes the binding (inhibits or promotes the binding) between the peptide of the present invention and the G protein-coupled receptor (APJ), and specifically, stimulates cells via the G protein-coupled receptor. A compound having an activity or a salt thereof (a so-called G protein-coupled receptor agonist) or a compound having no stimulating activity (a so-called G protein-coupled receptor antagonist). Such compounds include peptides, proteins, non-peptidic compounds, synthetic compounds,
Fermentation products and the like may be mentioned, and these compounds may be novel compounds or known compounds.

A specific method for evaluating whether the compound is a G protein-coupled receptor agonist or antagonist may be in accordance with the following (i) or (ii). (I) The binding assay shown in the above screening method (1) is performed, and the peptide of the present invention and G
After obtaining a compound that changes the binding property to protein-coupled receptor (APJ) (particularly, inhibits the binding), the compound has the above-mentioned cell stimulating activity via G protein-coupled receptor (APJ). Measure whether or not. A compound having a cell stimulating activity or a salt thereof is a G protein-coupled receptor agonist, and a compound having no such activity or a salt thereof is a G protein-coupled receptor antagonist. (Ii) (a) A test compound is brought into contact with cells containing a G protein-coupled receptor protein (APJ), and the cell stimulating activity via the G protein-coupled receptor (APJ) is measured. The compound having a cell stimulating activity or a salt thereof is G
It is a protein-coupled receptor agonist. (b) a case where a compound that activates a G protein-coupled receptor (for example, the peptide of the present invention or a G protein-coupled receptor agonist) is brought into contact with a cell containing a G protein-coupled receptor protein (APJ); , A compound that activates a G protein-coupled receptor (APJ) and a test compound are identified as G protein-coupled receptor protein (A
The cell stimulating activity via the G protein-coupled receptor (APJ) when contacted with a cell containing (PJ) is measured and compared. G protein-coupled receptor (AP
The compound capable of decreasing the cell stimulating activity of the compound activating J) or a salt thereof is a G protein-coupled receptor antagonist. The G protein-coupled receptor agonist is a G protein-coupled receptor protein (APJ)
Has the same action as the physiological activity of the peptide of the present invention, etc., and is therefore useful as a safe and low-toxic drug like the peptide of the present invention. Conversely, G protein-coupled receptor antagonists can suppress the physiological activity of the peptide of the present invention and the like against G protein-coupled receptor protein (APJ), and thus are safe and low-toxic drugs that suppress the receptor activity. Useful as The peptide or the like of the present invention has a central nervous function regulating action, a circulating function regulating action, a heart function regulating action, an immune function regulating action,
Since the above-mentioned agonists or antagonists are involved in gastrointestinal function control, metabolic function control or reproductive function control, etc., for example, senile dementia, cerebrovascular dementia, regressive metamorphic disease of systemic transformation (eg: Dementia and infectious diseases caused by Alzheimer's disease, Parkinson's disease, Pick's disease, Huntington's disease, etc. (eg late-onset viral infections such as Creutzfeldt-Jakob disease)
Dementia, endocrine, metabolic, or toxic diseases (eg:
Dementia due to hypothyroidism, vitamin B12 deficiency, alcohol intoxication, intoxication with various drugs, metals and organic compounds, dementia due to neoplastic disease (eg, brain tumor, etc.), traumatic disease (eg, chronic hard disease) Dementia such as dementia caused by submembrane hematoma), depression, hyperactive child (microbrain disorder) syndrome, consciousness disorder, anxiety disorder, schizophrenia, phobia, impaired growth hormone secretion (eg, giantosis, acromegaly) Bulimia, bulimia, bulimia, hypercholesterolemia, hyperglyceridemia, hyperlipidemia, hyperprolactinemia, hypoglycemia, hypopituitarism, pituitary dwarfism, diabetes ( Examples: diabetic complications, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, etc.), cancer (eg, breast cancer, lymphocytic leukemia, lung cancer, bladder cancer, ovarian cancer, prostate cancer, etc.), pancreatitis, kidney Diseases (eg, chronic renal failure, nephritis, etc.) Turner's syndrome, neurosis, rheumatoid arthritis, spinal cord injury, transient ischemic attack, amyotrophic lateral sclerosis, acute myocardial infarction, spinocerebellar degeneration, fracture, wound,
It can be used as a therapeutic / prophylactic agent for diseases such as atopic dermatitis, osteoporosis, asthma, epilepsy, infertility, arteriosclerosis, emphysema, pulmonary edema or lactation deficiency. Furthermore, it can be used as a hypnotic sedative, post-operative nutritional condition improver, vasopressor, antihypertensive, and the like. In addition, HIV infection, AIDS (AIDS (Acquired Immune Deficiency)
Syndrome): It can be used as a therapeutic / prophylactic agent for acquired immunodeficiency syndrome). As a salt of the compound obtained by using the above-described screening method or screening kit, for example, a pharmaceutically acceptable salt or the like is used. Examples include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.

Preferred examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and aluminum salt and ammonium salt. . Preferred examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzylethylenediamine And salt. Suitable examples of salts with inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid,
Salts with phosphoric acid and the like can be mentioned. Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, propionic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid And the like. Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ortin, and preferable examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. When a compound or a salt thereof obtained by using the screening method or the screening kit of the present invention is used as the above-mentioned medicine, it can be carried out in the same manner as when the above-mentioned peptide or the like of the present invention is used as a medicine.

In the present specification and drawings, when bases and amino acids are represented by abbreviations, IUPAC-IUB
It is based on the abbreviation by the Commission on Biochemical Nomenclature or the abbreviation commonly used in the relevant field, examples of which are described below. When an amino acid can have an optical isomer, the L-form is indicated unless otherwise specified. DNA: deoxyribonucleic acid cDNA: complementary deoxyribonucleic acid A: adenine T: thymine G: guanine C: cytosine Y: thymine or cytosine N: thymine, cytosine, adenine or guanine R: adenine or guanine M: cytosine or adenine W: thymine or adenine Adenine S: cytosine or guanine RNA: ribonucleic acid mRNA: messenger ribonucleic acid dATP: deoxyadenosine triphosphate dTTP: deoxythymidine triphosphate dGTP: deoxyguanosine triphosphate dCTP: deoxycytidine triphosphate ATP: adenosine triphosphate EDTA : Ethylenediaminetetraacetic acid SDS: Sodium dodecyl sulfate EIA: Enzyme immunoassay Gly or G: Glycine Ala or A: Alanine Val Or V: Valine Leu or L: Leucine Ile or I: Isoleucine Ser or S: Serine Thr or T: Threonine Cys or C: Cysteine Met or M: Methionine Glu or E: Glutamic acid Asp or D: Aspartic acid Lys or K: Lysine Arg or R: Arginine His or H: Histidine Phe or F: Phenylalanine Tyr or Y: Tyrosine Trp or W: Tryptophan Pro or P: Proline Asn or N: Asparagine Gln or Q: Glutamine pGlu: eGlutamic acid M: Pyroglutamic acid M : Ethyl group Bu: butyl group Ph: phenyl group Nle: norleucine Thi: 2-thienylalanine Phg: phenylglycine Pya (2) : 2-pyridylalanine Adi (NH _2): 2-aminoadipic acid -6 amide Hyp: oxyproline (hydroxyproline) ^Ac-Arg: N α - acetyl arginine ^Lys (Ac): N ε - acetyl lysine Lys (Me) : N ^epsilon - methyl lysine Lys ^(Tos): N ε - Toshirurijin Arg ^(Tos): N ε - tosyl-arginine Phe (Cl): 4- chlorophenylalanine Nal (2): 2- naphthylalanine Cha: cyclohexylalanine Met (O) : Methionine sulfoxide Tyr (Me): O-methyltyrosine Tyr (I): 3-iodotyrosine

The substituents, protecting groups and reagents frequently used in the present specification are represented by the following symbols. Tos: p-toluenesulfonyl HONB: N-hydroxy-5-norbornene-2,3-dicarboxyimide Bzl: benzyl Z: benzyloxycarbonyl Br-Z: 2-bromobenzyloxycarbonyl Cl-Z: 2-chlorobenzyloxycarbonyl Boc : T-butyloxycarbonyl HOBt: 1-hydroxybenztriazole DCC: N, N'-dicyclohexylcarbodiimide TFA: trifluoroacetic acid Fmoc: N-9-fluorenylmethoxycarbonyl DNP: dinitrophenyl Bum: tert-butoxymethyl Trt: Trityl Pbf: 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl HOOBt: 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotri Zin TFE: trifluoroethanol HOAt: 1-hydroxy-7-azabenzotriazole PyBrop: bromotrispirolidinophosphonium hexafluorophosphate TMS-Br: trimethylsilyl bromide TC: thiazolidine-4 (R) -carboxamide group Bom: benzyloxymethyl NMP: N-methylpyrrolidone PAM: phenylacetamidomethyl DCM: dichloromethane DMF: N, N-dimethylformamide DIEA: N, N-diisopropylethylamine Clt: 2-chlorotrityl the For: formyl Lys (Arg-Arg): N ε - alginate sulfonyl arginyl lysine AM: aminomethyl Pyn: 1-Pireniruaranin Mor: morpholin N-MeAla: N-methyl-alanine ^{_{Lys (Me) 2: N ε}} - dimethyl Jin Dap: diaminopropionic acid Mmt: 4-methoxytrityl Adi: adipoyl ^{_{Dap (C 6): N β}} - hexanoyl-diaminopropionic acid DIPCDI: N, N'-di-iso pyromellitic pills Carnot diimide NMe2: dimethylamine Dap (Ac) : N ^beta - acetylamino-diaminopropionic acid Dap (Adi): ^N β - adipoyl-aminopropionic acid

The sequence numbers in the sequence listing in the present specification indicate the following sequences. [SEQ ID NO: 1] This shows the amino acid sequence of the peptide obtained in Example 1 described later. [SEQ ID NO: 2] This shows the amino acid sequence of the peptide obtained in Example 2 described later. [SEQ ID NO: 3] This shows the amino acid sequence of the peptide obtained in Example 3 described later. [SEQ ID NO: 4] This shows the amino acid sequence of the peptide obtained in Example 4 described later. [SEQ ID NO: 5] This shows the amino acid sequence of the peptide obtained in Example 5 described later. [SEQ ID NO: 6] This shows the amino acid sequence of the peptide obtained in Example 6 described later. [SEQ ID NO: 7] This shows the amino acid sequence of the peptide obtained in Example 7 described later. [SEQ ID NO: 8] This shows the amino acid sequence of the peptide obtained in Example 8 described later. [SEQ ID NO: 9] This shows the amino acid sequence of the peptide obtained in Example 9 described later. [SEQ ID NO: 10] This shows the amino acid sequence of the peptide obtained in Example 10 described later. [SEQ ID NO: 11] This shows the amino acid sequence of the peptide obtained in Example 11 described later. [SEQ ID NO: 12] This shows the amino acid sequence of the peptide obtained in Example 12 described later. [SEQ ID NO: 13] This shows the amino acid sequence of the peptide obtained in Example 13 described later. [SEQ ID NO: 14] This shows the amino acid sequence of the peptide obtained in Example 14 described later. [SEQ ID NO: 15] This shows the amino acid sequence of the peptide obtained in Example 15 described later. [SEQ ID NO: 16] This shows the amino acid sequence of the peptide obtained in Example 16 described later. [SEQ ID NO: 17] This shows the amino acid sequence of the peptide obtained in Reference Example 1 described later. [SEQ ID NO: 18] This shows the amino acid sequence of the peptide obtained in Reference Example 2 described later. [SEQ ID NO: 19] This shows the amino acid sequence of APJ. [SEQ ID NO: 20] This shows the base sequence of DNA encoding the amino acid sequence of SEQ ID NO: 19. [SEQ ID NO: 21] This shows the amino acid sequence of the peptide obtained in Example 17 described later. [SEQ ID NO: 22] This shows the amino acid sequence of the peptide obtained in Example 18 described later. [SEQ ID NO: 23] This shows the amino acid sequence of the peptide obtained in Example 19 described later. [SEQ ID NO: 24] This shows the amino acid sequence of the peptide obtained in Example 20 described later. [SEQ ID NO: 25] This shows the amino acid sequence of the peptide obtained in Example 21 described later. [SEQ ID NO: 26] This shows the amino acid sequence of the peptide obtained in Example 22 described later. [SEQ ID NO: 27] This shows the amino acid sequence of the peptide obtained in Example 23 described later. [SEQ ID NO: 28] This shows the amino acid sequence of the peptide obtained in Example 24 described later. [SEQ ID NO: 29] This shows the amino acid sequence of the peptide obtained in Example 25 described later. [SEQ ID NO: 30] This shows the amino acid sequence of the peptide obtained in Example 26 described later. [SEQ ID NO: 31] This shows the amino acid sequence of the peptide obtained in Example 27 described later. [SEQ ID NO: 32] This shows the amino acid sequence of the peptide obtained in Example 28 described later. [SEQ ID NO: 33] This shows the amino acid sequence of the peptide obtained in Example 29 described later. [SEQ ID NO: 34] This shows the amino acid sequence of the peptide obtained in Example 30 described later. [SEQ ID NO: 35] This shows the amino acid sequence of the peptide obtained in Example 31 described later. [SEQ ID NO: 36] This shows the amino acid sequence of the peptide obtained in Example 32 described later. [SEQ ID NO: 37] This shows the amino acid sequence of the peptide obtained in Example 33 described later. [SEQ ID NO: 38] This shows the amino acid sequence of the peptide obtained in Example 34 described later. [SEQ ID NO: 39] This shows the amino acid sequence of the peptide obtained in Example 35 described later. [SEQ ID NO: 40] This shows the amino acid sequence of the peptide obtained in Example 36 described later. [SEQ ID NO: 41] This shows the amino acid sequence of the peptide obtained in Example 37 described later. [SEQ ID NO: 42] This shows the amino acid sequence of the peptide obtained in Example 38 described later. [SEQ ID NO: 43] This shows the amino acid sequence of the peptide obtained in Example 39 described later. [SEQ ID NO: 44] This shows the amino acid sequence of the peptide obtained in Example 40 described later. [SEQ ID NO: 45] This shows the amino acid sequence of the peptide obtained in Example 41 described later. [SEQ ID NO: 46] This shows the amino acid sequence of the peptide obtained in Example 42 described later. [SEQ ID NO: 47] This shows the amino acid sequence of the peptide obtained in Example 43 described later. [SEQ ID NO: 48] This shows the amino acid sequence of the peptide obtained in Example 44 described later. [SEQ ID NO: 49] This shows the amino acid sequence of the peptide obtained in Example 45 described later. [SEQ ID NO: 50] This shows the amino acid sequence of the peptide obtained in Example 46 described later. [SEQ ID NO: 51] This shows the amino acid sequence of the peptide obtained in Example 47 described later. [SEQ ID NO: 52] This shows the amino acid sequence of the peptide obtained in Example 48 described later. [SEQ ID NO: 53] This shows the amino acid sequence of the peptide obtained in Example 49 described later. [SEQ ID NO: 54] This shows the amino acid sequence of the peptide obtained in Example 50 described later. [SEQ ID NO: 55] This shows the amino acid sequence of the peptide obtained in Example 51 described later. [SEQ ID NO: 56] This shows the amino acid sequence of the peptide obtained in Example 52 described later. [SEQ ID NO: 57] This shows the amino acid sequence of the peptide obtained in Example 53 described later. [SEQ ID NO: 58] This shows the amino acid sequence of the peptide obtained in Example 54 described later. [SEQ ID NO: 59] This shows the amino acid sequence of the peptide obtained in Example 55 described later. [SEQ ID NO: 60] This shows the amino acid sequence of the peptide obtained in Example 56 described later. [SEQ ID NO: 61] This shows the amino acid sequence of the peptide obtained in Example 57 described later. [SEQ ID NO: 62] This shows the amino acid sequence of the peptide obtained in Example 58 described later. [SEQ ID NO: 63] This shows the amino acid sequence of the peptide obtained in Example 59 described later. [SEQ ID NO: 64] This shows the amino acid sequence of the peptide obtained in Example 60 described later. [SEQ ID NO: 65] This shows the amino acid sequence of the peptide obtained in Example 61 described later. [SEQ ID NO: 66] This shows the amino acid sequence of the peptide obtained in Example 62 described later. [SEQ ID NO: 67] This shows the amino acid sequence of the peptide obtained in Example 63 described later. [SEQ ID NO: 68] This shows the amino acid sequence of the peptide obtained in Example 64 described later. [SEQ ID NO: 69] This shows the amino acid sequence of the peptide obtained in Example 65 described later. [SEQ ID NO: 70] This shows the amino acid sequence of the peptide obtained in Example 66 described later. [SEQ ID NO: 71] This shows the amino acid sequence of the peptide obtained in Example 67 described later. [SEQ ID NO: 72] This shows the amino acid sequence of the peptide obtained in Example 68 described later.

[0044]

EXAMPLES The present invention will be described in more detail with reference to Reference Examples, Examples and Experimental Examples, which do not limit the scope of the present invention.

Example 1 Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Me
Production of t-Pro-Phe (Cl) (SEQ ID NO: 1) Commercially available 2-chlorotrityl resin (Clt resin, 1.22 mmol / g)
Fmoc-Phe (Cl) -O-Clt res introduced with Fmoc-Phe (Cl) -OH
in (0.495 mmol / g) 0.25 mmol of the peptide synthesizer ABI 433
Solid phase synthesis was performed using the Fmoc / DCC / HOBt method in the reaction soda of A. The side chain protecting group of Fmoc amino acid is Pbf for Arg
Group, Ser used tBu group, and Gln used Trt group. The other amino acids used were unprotected in the side chain, and peptide chains were introduced sequentially from Pro in the sequence shown above toward the N-terminus to obtain the desired protected peptide resin. 200 mg (39.8 mmol) of this resin was added to TFA, thioanis
ole, m-cresol, H ₂ O, ethanedithiol, triisopropylsil
After stirring for 2 hours at room temperature in 3 ml of a mixture of ane (80: 5: 5: 5: 2.5: 2.5), ether was added to the reaction solution, white powder was precipitated, centrifuged, and the operation of removing the supernatant was performed. Repeated three times. The residue was extracted with water and freeze-dried to give 91.7 white powder.
mg was obtained. 52.2 mg of the obtained crude peptide was used in TSK GEL ODS 1
Preparative HPLC using a 20T column (20 x 300 mm), solution A: 0.1
% TFA-water, solution B: A / B with acetonitrile containing 0.1% TFA:
A linear concentration gradient elution was performed from 81/19 to 71/29 (60 minutes), and the fractions containing the target compound were collected and freeze-dried to obtain 15.5 mg of a white powder. (M + H) by mass spectrometry ⁺ 1858.7 (calculated value 1859.0) HPLC elution time 19.7 min Elution conditions Column YMC ODS AM-301, S-5μm, 120A (4.6 x 100mm) Eluent A solution: 0.1% TFA-water, Solution B: Using acetonitrile containing 0.1% TFA, A / B: linear concentration gradient elution from 100/0 to 50/50 (25 minutes) Flow rate 1.0 ml / min

The compounds of Examples 2 to 16 and Reference Example 1 were produced by the same solid phase synthesis, deprotection and purification as in Example 1. (M + H) ⁺ value (measured and calculated) of each compound by mass spectrometry and HPLC retention time
(Minutes) are shown in Table 1. Compound of Example 2: Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Ch
a-Pro-Phe (Cl) (SEQ ID NO: 2) Compound of Example 3: Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Met-Pro-Phe (C
l) (SEQ ID NO: 3) Compound of Example 4: Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Cha-Phe (Cl)
(SEQ ID NO: 4) Compound of Example 5: Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Cha-Pro-Phe (C
l) (SEQ ID NO: 5) Compound of Example 6: Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Ch
a (SEQ ID NO: 6) Compound of Example 7: Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Cha-Pro-Phe (C
l) (SEQ ID NO: 7) Compound of Example 8: Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe (C
l) (SEQ ID NO: 8) Compound of Example 9: pGlu-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Cha-Pro-P
he (SEQ ID NO: 9) Compound of Example 10: pGlu-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-P
he (Cl) (SEQ ID NO: 10) Compound of Example 11: Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Cha-Pro-Phe
(SEQ ID NO: 11) Compound of Example 12: Arg-Pro-Arg-Leu-Phe-Ala-Arg-Gly-Pro-Cha-Pro-Phe (C
l) (SEQ ID NO: 12) Compound of Example 13: Arg-Pro-Arg-Leu-Phe-His-Lys-Gly-Pro-Cha-Pro-Phe (C
l) (SEQ ID NO: 13) Compound of Example 14: Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Nl
e-Pro-Tyr (SEQ ID NO: 14) Compound of Example 15: Arg-Pro-Arg-Leu-Phe-His-Lys-Gly-Pro-Cha-Pro-Phe
(SEQ ID NO: 15) Compound of Example 16: Arg-Pro-Arg-Leu-Phe-His-Lys-Gly-Pro-Met-Pro-Phe (C
l) (SEQ ID NO: 16) Compound of Reference Example 1: Leu-Val-Gln-Pro-Arg-Gly-Ser-Arg-Asn-Gly-Pro-Gly-Pr
o-Trp-Gln-Gly-Gly-Arg-Arg-Lys-Phe-Arg-Arg-Gln-Arg-
Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Nle-Pro-Tyr (SEQ ID NO: 17)

[0047]

[Table 1]

The same solid-phase synthesis, deprotection and purification as in Example 1 were carried out, and Examples 17 to 19, 21 to 46 and 48 to 5 were performed.
Compound No. 0 was obtained. By mass spectrometry of each compound
(M + H) ⁺ value (measured and calculated) and HPLC retention time
(Minutes) are shown in Table 2. Compound of Example 17: Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Me
t-Pro-Phe (SEQ ID NO: 21) Compound of Example 18: Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Me
t (SEQ ID NO: 22) Compound of Example 19: Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro
(SEQ ID NO: 23) Compound of Example 21: Arg-Arg-Lys (Arg-Arg) -Arg-Pro-Arg-Leu-Ser-His-Lys-G
ly-Pro-Met-Pro-Phe (SEQ ID NO: 25) Compound of Example 22: Arg-Arg-Arg-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Me
t-Pro-Phe (SEQ ID NO: 26) Compound of Example 23: Arg-Arg-Lys-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Me
t-Pro-Phe (SEQ ID NO: 27) Compound of Example 24: Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Met-Pro-Phe
(SEQ ID NO: 28) Compound of Example 25: Arg-Arg-Ala-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Me
t-Pro-Phe (SEQ ID NO: 29) Compound of Example 26: pGlu-Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Met-Pro-P
he (SEQ ID NO: 30) Compound of Example 27: Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Met (SEQ ID NO: 31) Compound of Example 28: Arg-Pro-Arg- Leu-Ser-His-Lys-Gly-Pro-Met-Phe (Cl)
(SEQ ID NO: 32) Compound of Example 29: pGlu-Arg-Pro-Arg-Leu-Ser-Ala-Lys-Gly-Pro-Met-Pro-P
he (SEQ ID NO: 33) Compound of Example 30: pGlu-Arg-Pro-Arg-Leu-Ser-Arg-Lys-Gly-Pro-Met-Pro-P
he (SEQ ID NO: 34) Compound of Example 31: Arg-Pro-Arg-Leu-Phe-Ala-Arg-Gly-Pro-Met-Pro-Phe
(SEQ ID NO: 35) Compound of Example 32: Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Nal (2)
(SEQ ID NO: 36) Compound of Example 33: Arg-Arg-Phe-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Me
t-Pro-Phe (SEQ ID NO: 37) Compound of Example 34: pGlu-Arg-Pro-Arg-Leu-Ser-His-Arg-Gly-Pro-Met-Pro-P
he (SEQ ID NO: 38) Compound of Example 35: pGlu-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Phe (C
l) (SEQ ID NO: 39) Compound of Example 36: Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Cha (SEQ ID NO: 40) Compound of Example 37: Arg-Pro -Arg-Leu-Phe-His-Lys-Gly-Pro-Cha-Phe (Cl)
(SEQ ID NO: 41) Compound of Example 38: pGlu-Arg-Pro-Arg-Leu-Ser-Leu-Lys-Gly-Pro-Met-Pro-P
he (SEQ ID NO: 42) Compound of Example 39: pGlu-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-N
al (2) (SEQ ID NO: 43) Compound of Example 40: Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Nal (2) (SEQ ID NO: 44) Compound: pGlu-Arg-Pro-Arg-Leu-Ser-Arg-Arg-Gly-Pro-Met-Pro-P
he (SEQ ID NO: 45) Compound of Example 42: pGlu-Arg-Pro-Arg-Leu-Phe-Arg-Arg-Gly-Pro-Met-Pro-P
he (SEQ ID NO: 46) Compound of Example 43: pGlu-Arg-Pro-Arg-Leu-Ser-Phe-Lys-Gly-Pro-Met-Pro-P
he (SEQ ID NO: 47) Compound of Example 44: pGlu-Arg-Pro-Arg-Leu-Phe-His-Lys-Gly-Pro-Met-Pro-P
he (SEQ ID NO: 48) Compound of Example 45: pGlu-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Cha
(SEQ ID NO: 49) Compound of Example 46: pGlu-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Nal
(2) (SEQ ID NO: 50) Compound of Example 48: pGlu-Arg-Pro-Arg-Leu-Ser-His-Phe-Gly-Pro-Met-Pro-P
he (SEQ ID NO: 52) Compound of Example 49: Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Cha
(SEQ ID NO: 53) Compound of Example 50: pGlu-Arg-Pro-Arg-Leu-Ser-His-Leu-Gly-Pro-Met-Pro-P
he (SEQ ID NO: 54)

[0049]

[Table 2]

Example 20 Arg-Arg-Gln-Arg-Pro-Arg-Le
Production of u-Ser-His-Lys-Gly-Pro-Met (O) (SEQ ID NO: 24) 20 mg of the crude peptide obtained by the same method as in Example 1 described above was used for LiChroprep (trade name) RP-18. 200% 0.1% TFA water on a reversed phase chromatography column (2.6 x 60 cm) packed with
Then, linear gradient elution was performed using 300 ml of 0.1% TFA water and 300 ml of 33% acetonitrile water containing 0.1% TFA, and the target fraction was collected and lyophilized to obtain 30 mg of a white powder. By mass spectrometry (M + H) ⁺ 1634.9 (calculated value 1634.9) HPLC elution time 14.03 min Elution conditions Column Wakosil5C18T (4.6 x 100 mm) Eluent A solution: 0.1% TFA-water, B solution: acetonitrile containing 0.1% TFA A / B: 55/95 to 55/45 using linear gradient elution (25 min) Flow rate: 1.0 ml / min

Example 47 Arg-Pro-Arg-Leu-Phe-Ala-Ar
Production of g-Gly-Pro-Met-Phe (SEQ ID NO: 51) Preparative HPLC using a TSK GEL ODS120T column (20 × 300 mm) was used to obtain 15 mg of the crude peptide obtained in the same manner as in Example 1 described above. Solution A: 0.1% TFA-water, Solution B: A / B: Acetonitrile containing 0.1% TFA was subjected to linear concentration gradient elution from 81/19 to 71/29 (60 minutes), The resultant was collected and freeze-dried to obtain 10.5 mg of a white powder. (M + H) by mass spectrometry ⁺ 1347.5 (calculated value: 1347.7) HPLC elution time 15.81 minutes Elution conditions Column YMC ODS AM-301, S-5μm, 120A (4.6 x 100mm) Eluent A solution: 0.1% TFA- Water, liquid B: using acetonitrile containing 0.1% TFA, A / B: linear concentration gradient elution from 10/90 to 60/40 (25 minutes) Flow rate 1.0 ml / min

Reference Example 2 pGlu-Arg-Pro-Arg-Leu-Ser-His
Production of -Lys-Gly-Pro-Nle-Pro-Tyr (SEQ ID NO: 18) Commercially available 2-chlorotrityl resin (Clt resin, 1.3 mmol / g)
Fmoc-Gly-O-Clt resin (0.392 mm
ol / g) 0.25 mmol was placed in a reaction solution of a peptide synthesizer ABI 433A, and using the Fmoc / DCC / HOBt method, Fmoc-Lys (Boc), Fmo
c-His (Trt), Fmoc-Ser (tBu), Fmoc-Leu, Fmoc-Arg (Pbf),
Fmoc-Pro, Fmoc-Arg (Pbf) and Boc-Gln were introduced in this order to obtain the desired protected peptide resin. 1 g of this resin is added to AcOH: T
FE: DCM (1: 2: 7) After stirring at room temperature for 2 hours in 20 ml, the resin was removed by filtration, the solvent was distilled off, the residue was crystallized with ether, and the protected peptide (Boc-Gln-Arg (Pbf) -Pro -Arg (Pbf) -Le
362 mg of u-Ser (tBu) -His (Trt) -Lys (Boc) -Gly-OH were obtained.
Boc-Pro, Boc-Nle, and Boc-Pro were sequentially condensed with H-Tyr (Bzl) -OBzl.HCl to obtain 217.8 mg of Boc-Pro-Nle-Pro-Tyr (Bzl) -Bzl. Boc-Gln-Arg (Pbf) -Pro-Arg (Pbf) -Leu-Ser (tBu) -His
(Trt) -Lys (Boc) -Gly-OH 100mg and HOAt 8.04mg DCM: DMF
(4: 1) Dissolve in 1 ml, and add 38.5 μl of DIEA, PyBrop 3 under ice-cooling.
4.20mg, H-Pro-Nle-Pro-Tyr (Bzl) -OBzl ・ HCl (Boc-Pro-N
After treating le-Pro-Tyr (Bzl) -OBzl with 4N-HCl / dioxane (prepared), 62.2 mg was added, the ice bath was removed, and the mixture was stirred at room temperature for 1 hr. After citric acid crystals were added to the solution for neutralization, the solvent was distilled off, water was added, and the precipitated solid was extracted with chloroform.
The extract was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated saline, dried over anhydrous sodium sulfate, the solvent was distilled off, ether was added, the powder was collected by filtration, and further purified by reprecipitation from ethyl acetate and ether.
Boc-Gln-Arg (Pbf) -Pro-Arg (Pbf) -Leu-Ser (tBu) -His (Tr
t) -Lys (Boc) -Gly-Pro-Nle-Pro-Tyr (Bzl) -OBzl 122.27m
g was obtained. 63.6 mg of this protected peptide was added to thioanisole 108
9μl, m-cresol 122μl, triisopropylsilane 238.5μ
l, stirred in 4.7 ml of TFA at room temperature for 90 minutes, added with 1.23 ml of TMS-Br, stirred for 1 hour under ice-cooling, removed the ice bath, and further stirred on a water bath at 20 ° C for 1 hour. After the reaction, the reaction solution was distilled off, ether was added to the residue, white powder was precipitated, centrifuged, and the operation of removing the supernatant was repeated three times. The residue was extracted with water, freeze-dried, passed through a Sephadex G-25 gel filtration column using 50% aqueous acetic acid, and the main fraction was heated in 80% AcOH at 70 ° C for 2 hours.The solution was diluted with water. Lyophilized. The obtained crude peptide was fractionated using a TSK GEL ODS120T column (20 x 300 mm).
Solution A: Solution A: 0.1% TFA-water, Solution B: Acetonitrile containing 0.1% TFA, A / B: Linear concentration gradient elution from 85/15 to 75/25 (60 minutes), containing the target compound The fractions were collected and freeze-dried to obtain 29.18 mg of a white powder. (M + H) ⁺ 1532.0 by mass spectrometry (calculated value 1531.9) HPLC elution time 14.6 min Elution conditions Column Wakosil 5C18T (4.6 x 100 mm) Eluent A: 0.1% TFA-water, B: acetonitrile containing 0.1% TFA Use, A / B: 95/5 to 45/55, linear gradient elution (25 min) Flow rate 1.0 ml / min

Example 51 Arg-Arg-Gln-Arg-Pro-Arg-Le
Production of u-Ser-Ala-Arg-Gly-NMe ₂ (SEQ ID NO: 55) 1 g of commercially available 4-sulfamylbutyryl AM resin (1.09 mmol / g) was added to D
356 mg (1.199 mmol) of Fmoc-Gly-OH in MF, 567 mg of PyBOP (1.09
mmol) and DIEA 0.417 ml (2.398 mmol) for 30 minutes at room temperature. After filtration, the resin was washed with DMF and 1.03 ml of Ac2O in DMF (1
0.9 mmol) and 0.882 ml (10.9 mmol) of pyridine were reacted at room temperature for 2 hours. After washing and drying the resin with DMF and MeOH, the resin is piperidin
e, measure the absorbance of the free Fmoc group, and measure 1.0496 g (F
moc-Gly content: 0.295 mmol / g) Fmoc-Gly-4-sulfamylbut
yryl AM resin was obtained. Fmoc-Gly-4-sulfamylbutyryl
Solid phase synthesis was performed in the same manner as in Example 1 using AM resin, and after the introduction of the last Arg, the Fmoc group was replaced with a Boc group. After the resin was activated with ICH ₂ CN and DIEA in NMP, it was treated with 50% -NHMe ₂ water to remove the protected peptide. The peptide was converted to TFA, thioanisole, m-cresol, H ₂ O, ethan as in Example 1.
edithiol, triisopropylsilane (80: 5: 5: 5: 2.5
: 2.5), followed by HPLC purification in the same manner to obtain the desired product.

Example 52 Arg-Arg-Gln-Arg-Pro-Arg-Le
Production of u-Ser-Ala-Arg-Gly-Mor (SEQ ID NO: 56) The same treatment and purification were performed by replacing 50% -NHMe ₂ water of Example 51 with morpholine to obtain the desired product.

The solid phase synthesis, deprotection and purification were carried out in the same manner as in Example 1 to obtain the compounds of Examples 53 to 64. Example 53: Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Ala-Pro-Phe (C
l) (SEQ ID NO: 57) Example 54: Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Gly-Met-Pro-Phe (C
l) (SEQ ID NO: 58) Example 55: Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-N-MeAla-Met-Pro-Ph
e (Cl) (SEQ ID NO: 59) Example 56: Arg-Pro-Arg-Leu-Ser-His-Ala-Gly-Pro-Cha-Pro-Phe (C
l) (SEQ ID NO: 60) Example 57: Arg-Pro-Arg-Ala-Ser-His-Lys-Gly-Pro-Cha-Pro-Phe (C
l) (SEQ ID NO: 61) Example 58: Arg-Pro-Ala-Leu-Ser-His-Lys-Gly-Pro-Cha-Pro-Phe (C
l) (SEQ ID NO: 62) Example 59: Carboxyl terminus of the compound of Example 1 was amidated by a conventional method to give Arg-Arg-Gln-Arg-Pro-Arg-Leu-
To obtain a Ser-Ala-Arg-Gly- Pro-Met-Pro-Phe (Cl) -NH 2. Example 60: Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Cha-Pyn (SEQ ID NO: 63) Example 61: Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly -Pro-Cha-Pro-Pyn
(SEQ ID NO: 64) Example 62: Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Gly-Ch
a (SEQ ID NO: 65) Example 63: Arg-Pro-Lys (Me) ₂ -Leu-Ser-Ala-Arg-Gly-Pro-Met-Pro-P
he (SEQ ID NO: 66) Example 64: Arg-Pro-Arg-Leu-Ser-Ala-Lys (Me) ₂ -Gly-Pro-Met-Pro-P
he (SEQ ID NO: 67)

Example 65: Arg-Pro-Arg-Leu-Ser-Dap-A
Production of rg-Gly-Pro-Cha-Pro-Phe (Cl) (SEQ ID NO: 68) Commercially available Wang resin and Fmoc- having side chain amino groups protected with Mmt
Solid phase synthesis was performed in the same manner as in Example 1 using Dap (Mmt).
The obtained resin was treated and refined in the same manner as in Example 1 to obtain the desired product.

Example 66: Arg-Pro-Arg-Leu-Ser-Dap
(Ac) -Arg-Gly-Pro-Cha-Pro-Phe (Cl) (SEQ ID NO: 6
9) Preparation of the resin obtained in Example 65 using 1% TFA / 5% triisopropylsilane
/ 94% DCM to remove only the side chain protecting group Mmt of Dap,
After acetylation with acetic anhydride, the residue was treated and purified in the same manner as in Example 65 to obtain the desired product. Example 67: Arg-Pro-Arg-Leu-Ser-Dap (C ₆ ) -Arg-Gly
Preparation of -Pro-Cha-Pro-Phe (Cl) (SEQ ID NO: 70) Hexanoic acid and DIPCDI in place of acetic anhydride in Example 66
The amino group was modified with to give the desired product. Example 68: Arg-Pro-Arg-Leu-Ser-Dap (Adi) -Arg-Gl
Production of y-Pro-Cha-Pro-Phe (Cl) SEQ ID NO: 71) The desired product was obtained using adipic acid in place of hexanoic acid in Example 67. (M + H) ⁺ value (measured value and calculated value) by mass spectrometry and HPLC retention time of the compounds of Examples 51 to 68 above
(Minutes) are shown in Table 3.

[0058]

[Table 3]

Experimental Example 1 Measurement of Inhibitory Activity of Forskolin-Stimulated cAMP Production The CH described in Example 7 of WO 99/33976 (Japanese Patent Application No. 10-220853) was applied to a 24-well tissue culture plate.
O-A10 clone 6 cells were seeded at 3 × 10 ⁵ cells / well and cultured overnight. 0.2mM 3-isobutyl-1-methylxantine (IBM
X), Hanks' balanc containing 0.05% bovine serum albumin
ed salt solution (HBSS) was prepared as an assay buffer, and each well was washed twice with 500 μl of the assay buffer, followed by preincubation at 37 ° C. for 30 minutes. After further washing once with 500 μl of assay buffer, 500 μl of a sample dissolved in the assay buffer containing 1 μM forskolin was added to each well,
Incubation was performed at 37 ° C. for 30 minutes. Wells incubated with assay buffer without forskolin to determine the basal cAMP production (basal level) of the cells, and assay buffer supplemented with forskolin to determine the maximum cAMP production (maximum level) stimulated by forskolin The wells incubated with were prepared in the same manner. After the incubation, each well was washed once with 500 μl of an assay buffer, and then 500 μl of lysis buffer 1B attached to Amersham cAMP EIA system was added to each well to extract cAMP. According to the kit recipe, 100 μl of each extract
Was used to measure the amount of cAMP. The cAMP production inhibitory activity was determined by the maximum level and the wel
The difference (cAMP production suppression amount) of the cAMP amount of l is determined,
Moreover calculated as a percentage of cAMP production increases the amount of stimulation to forskolin (difference between maximum level and basal level), were determined and EC ₅₀ values from the dose response curve. Table 4 shows the activities of the compounds of Examples 1 to 16 measured by the method of Experimental Example 1, Table 5 shows the activities of the compounds of Examples 17 to 50 measured by the method of Experimental Example 1, and Table 6 Experimental example 1
5 shows the activities of the compounds of Examples 51 to 68 measured by the method described in Example 1.

[0060]

[Table 4]

[0061]

[Table 5]

[0062]

[Table 6]

Experimental Example 2 Receptor binding assay-1: The compound of Reference Example 1 was labeled with ¹²⁵ I by the lactoperoxidase method as follows to prepare a compound. For 20 μl of 0.1 mM aqueous solution of peptide, 0.1 M HEPE
20 μl of lactoperoxidase (Sigma) dissolved in S-NaOH / pH 7.0 at a concentration of 10 μg / ml, Iodine-125 (Amersh
Am Co., IMS-30, 74MBq) 20μl, 30% hydrogen peroxide solution (Wako Pure Chemical Industries) diluted 6000 times 20μl aqueous solution was added,
After mixing with a vortex mixer, the mixture was incubated at room temperature for 10 minutes. The reaction was stopped by adding 600 μl of distilled water containing 0.1% TFA, and then TSKgel ODS-80TM CTR 4.6 ×
Separation was performed by reverse-phase HPLC using a 100 mm column, and the peak portion of the label generated by the reaction was separated. Equal amounts of assay buffer (50 mM Tris-HCl / pH7.5, 5 mM EDTA,
0.5mMPMSF, 20μg / ml leupeptin, 0.1μg / ml pepstati
n A, 4μg / ml E-64 (Peptide Research Institute), 0.1%
Bovine serum albumin) and stored at -30 ° C until use. The CHO-A10 cells were cultured, and the cells were collected from the culture vessel using PBS containing 5 mM EDTA, and then suspended in the above-mentioned assay buffer containing no bovine serum albumin.
Using a Polytron homogenizer (Kinematica)
Homogenization was performed three times at 12,000 rpm for 15 seconds, and the supernatant after centrifugation (1000 × g, 4 ° C., 10 minutes) was collected. The same operation was performed again on the precipitate, and after collecting each supernatant, centrifugation was performed at 100,000 × g at 4 ° C. for 1 hour to collect the precipitate (membrane fraction). The membrane fraction was resuspended in a small amount of buffer, homogenized using a Teflon (registered trademark) homogenizer, and stored at -80 ° C until use. The binding assay was performed under the following conditions. A 100 μl solution containing 0.25 μg of the membrane fraction, a final concentration of 100 pM ¹²⁵ I-labeled compound, an analyte, and an assay buffer was prepared in a polypropylene 96-well plate, and incubated at room temperature for 1.5 hours. Measuring non-specific binding instead of sample
This was performed using wells to which 1 μM of the unlabeled compound had been added. After the incubation is completed, the cell harvester (Packard) and the filter unit (GF
/ C, Packard) and the membrane fraction was collected on a filter. After the filter was sufficiently dried, Microcinti O (Packard) was added, and the amount of the label collected together with the membrane fraction on the filter was measured using Topcount (Packard). After subtracting the non-specific binding amount from each measured value, the ratio of the amount of binding decreased by the addition of the sample (inhibition rate) to the wells (total binding amount) to which the sample was not added was calculated. -
IC ₅₀ values were calculated from the inhibition curves (Table 7 Table 9).

[0064]

[Table 7]

[0065]

[Table 8]

[0066]

[Table 9]

[0067] Experimental Example 3 Receptor Binding Assay -2: dose of each specimen in the same manner as Example 2 using the compound of Reference Example 2 - IC ₅₀ values were calculated from the inhibition curves (Table 10
Table 12).

[0068]

[Table 10]

[0069]

[Table 11]

[0070]

[Table 12]

[0071]

Industrial Applicability The peptide derivative of the present invention is involved in central nervous system function control, circulatory function control, heart function control, immune function control, gastrointestinal function control, metabolic function control or genital function control. Therefore, the above-mentioned agonists or antagonists may be used for senile dementia, cerebrovascular dementia, degenerative metamorphic diseases such as phylogenic variants (eg, Alzheimer's disease, Parkinson's disease, Pick's disease, Huntington's disease, etc.) Dementia, endocrine, metabolic, or toxic diseases (eg, hypothyroidism, vitamin B12 deficiency, alcoholism, various types of infectious diseases (eg, late viral infections such as Creutzfeldt-Jakob disease)) Dementia due to poisoning by drugs, metals and organic compounds, etc., dementia due to neoplastic diseases (eg brain tumors) , Traumatic diseases: dementia, such as dementia caused by (eg chronic such subdural hematoma), depression, hyperactive children (fine encephalopathy) syndrome, disturbance of consciousness, anxiety disorder, schizophrenia,
Phobia, impaired growth hormone secretion (eg, gigantism, acromegaly, etc.), bulimia, bulimia, hypercholesterolemia, hyperglyceridemia, hyperlipidemia, hyperprolactinemia, hypoglycemia, Hypopituitarism, pituitary dwarfism, diabetes (eg diabetic complications, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, etc.), cancer (eg breast cancer, lymphocytic leukemia, lung cancer , Bladder cancer, ovarian cancer, prostate cancer, etc.), pancreatitis,
Renal disease (eg, chronic renal failure, nephritis, etc.), Turner syndrome, neurosis, rheumatoid arthritis, spinal cord injury, transient cerebral ischemic attack, amyotrophic lateral sclerosis, acute myocardial infarction, spinocerebellar degeneration, It can be used as a therapeutic / prophylactic agent for diseases such as fractures, wounds, atopic dermatitis, osteoporosis, asthma, epilepsy, infertility, arteriosclerosis, emphysema, pulmonary edema or lactation deficiency. Furthermore, it can be used as a hypnotic sedative, post-operative nutritional condition improver, vasopressor, antihypertensive, and the like. In addition, HIV infections, AIDS (AIDS (Acquir
ed Immune Deficiency Syndrome): It can be used as a therapeutic / prophylactic agent for acquired immunodeficiency syndrome).

[0072]

[Sequence Listing] [Sequence Listing] <110> Takeda Chemical Industries, Ltd. <120> Peptide derivative <130> B01111 <150> JP 12-87114 <151> 2000-03-23 <150> JP 12-288891 <151 > 2000-09-19 <160> 72 <210> 1 <211> 15 <212> PRT <213> Artificial Sequence <223> Xaa means Phe (Cl) <400> 1 Arg Arg Gln Arg Pro Arg Leu Ser Ala Arg Gly Pro Met Pro Xaa 1 5 10 15 <210> 2 <211> 15 <212> PRT <213> Artificial Sequence <223> Xaa on the 13th position means Cha, Xaa on the 15th position means Phe (Cl) <400> 2 Arg Arg Gln Arg Pro Arg Leu Ser His Lys Gly Pro Cha Pro Xaa 1 5 10 15 <210> 3 <211> 12 <212> PRT <213> Artificial Sequence <223> Xaa means Phe (Cl) <400> 3 Arg Pro Arg Leu Ser Ala Arg Gly Pro Met Pro Xaa 1 5 10 <210> 4 <211> 11 <212> PRT <213> Artificial Sequence <223> Xaa on the 10th position means Cha, Xaa on the 11th position means Phe (Cl). <400> 4 Arg Pro Arg Leu Ser Ala Arg Gly Pro Xaa Xaa 1 5 10 <210> 5 <211> 12 <212> PRT <213> Artificial Sequence <223> Xaa on the 10th position means Cha, Xaa on the 1 2th position means Phe (Cl). <400> 5 Arg Pro Arg Leu Ser Ala Arg Gly Pro Xaa Pro Xaa 1 5 10 <210> 6 <211> 13 <212> PRT <213> Artificial Sequence <223> Xaa means Cha <400> 6 Arg Arg Gln Arg Pro Arg Leu Ser Ala Arg Gly Pro Cha 1 5 10 <210> 7 <211> 12 <212> PRT <213> Artificial Sequence <223> Xaa on the 10th position means Cha, Xaa on the 12th position means Phe (Cl). <400> 7 Arg Pro Arg Leu Ser His Lys Gly Pro Xaa Pro Xaa 1 5 10 <210> 8 <211> 12 <212> PRT <213> Artificial Sequence <223> Xaa means Phe (Cl). <400> 8 Arg Pro Arg Leu Ser His Lys Gly Pro Met Pro Xaa 1 5 10 <210> 9 <211> 13 <212> PRT <213> Artificial Sequence <223> Xaa on the 1st position means pGlu, Xaa on the 11th position means Cha. <400> 9 Xaa Arg Pro Arg Leu Ser His Lys Gly Pro Xaa Pro Phe 1 5 10 <210> 10 <211> 13 <212> PRT <213> Artificial Sequence <223 > Xaa on the 1st position means pGlu, Xaa on the 13th position means Phe (Cl). <400> 10 Xaa Arg Pro Arg Leu Ser His Lys Gly Pro Met Pro Xaa 1 5 10 <210> 11 <211> 12 <212 > PRT <213> Artificial Sequence <223> Xaa means Cha. <400> 11 Arg Pro Arg Leu Ser Ala Arg Gly Pro Xaa Pro Phe 1 5 10 <210> 12 <211> 12 <212> PRT <213> Artificial Sequence <223 > Xaa on the 10th position means Cha, Xaa on the 12th position means Phe (Cl). <400> 12 Arg Pro Arg Leu Phe Ala Arg Gly Pro Xaa Pro Xaa 1 5 10 <210> 13 <211> 12 <212> PRT <213> Artificial Sequence <223> Xaa on the 10th position means Cha, Xaa on the 12th position means Phe (Cl). <400> 13 Arg Pro Arg Leu Phe His Lys Gly Pro Xaa Pro Xaa 1 5 10 <210> 14 <211> 15 <212> PRT <213> Artificial Sequence <223> Xaa means Nle. <400> 14 Arg Arg Gln Arg Pro Arg Leu Ser His Lys Gly Pro Xaa Pro Tyr 1 5 10 15 <210> 15 <211 > 12 <212> PRT <213> Artificial Sequence <223> Xaa means Cha. <400> 15 Arg Pro Arg Leu Phe His Lys Gly Pro Xaa Pro Phe 1 5 10 <210> 16 <211> 12 <212> PRT <213> Artificial Sequence <223> Xaa means Phe (Cl). <400> 16 Arg Pro Arg Leu Phe His Lys Gly Pro Met Pro Xaa 1 5 10 <210> 17 <211> 36 <212> PRT <213> Artificial Sequenc e <223> Xaa means Nle. <400> 17 Leu Val Gln Pro Arg Gly Ser Arg Asn Gly Pro Gly Pro Trp Gln Gly 1 5 10 15 Gly Arg Arg Lys Phe Arg Arg Gln Arg Pro Arg Leu Ser His Lys Gly 20 25 30 Pro Xaa Pro Tyr 35 <210> 18 <211> 13 <212> PRT <213> Artificial Sequence <223> Xaa on the 1st position means pGlu, Xaa on the 11th position means Nle. <400> 18 Xaa Arg Pro Arg Leu Ser His Lys Gly Pro Xaa Pro Tyr 1 5 10 <210> 19 <211> 380 <212> PRT <213> Unknown <220><223><400> 19 Met Glu Glu Gly Gly Asp Phe Asp Asn Tyr Tyr Gly Ala Asp Asn Gln 1 5 10 15 Ser Glu Cys Glu Tyr Thr Asp Trp Lys Ser Ser Gly Ala Leu Ile Pro 20 25 30 Ala Ile Tyr Met Leu Val Phe Leu Leu Gly Thr Thr Gly Asn Gly Leu 35 40 45 Val Leu Trp Thr Val Phe Arg Ser Ser Arg Glu Lys Arg Arg Ser Ala 50 55 60 Asp Ile Phe Ile Ala Ser Leu Ala Val Ala Asp Leu Thr Phe Val Val 65 70 75 80 Thr Leu Pro Leu Trp Ala Thr Tyr Thr Tyr Arg Asp Tyr Asp Trp Pro 85 90 95 Phe Gly Thr Phe Phe Cys Lys Leu Ser Ser Tyr Leu Ile Phe Val Asn 100 105 110 Met Tyr Ala Ser Val Phe Cys Leu Thr Gly Leu Ser Phe Asp Arg Tyr 115 120 125 Leu Ala Ile Val Arg Pro Val Ala Asn Ala Arg Leu Arg Leu Arg Val 130 135 140 Ser Gly Ala Val Ala Thr Ala Val Leu Trp Val Leu Ala 145 150 155 160 Ala Met Pro Val Met Val Leu Arg Thr Thr Gly Asp Leu Glu Asn Thr 165 170 175 Thr Lys Val Gln Cys Tyr Met Asp Tyr Ser Met Val Ala Thr Val Ser 180 185 190 Ser Glu Trp Ala Trp Glu Val Gly Leu Gly Val Ser Ser Thr Thr Val Val 195 200 205 Gly Phe Val Val Pro Phe Thr Ile Met Leu Thr Cys Tyr Phe Phe Ile 210 215 220 Ala Gln Thr Ile Ala Gly His Phe Arg Lys Glu Arg Ile Glu Gly Leu 225 230 235 240 Arg Lys Arg Arg Arg Leu Leu Ser Ile Ile Val Val Leu Val Val Thr 245 250 255 Phe Ala Leu Cys Trp Met Pro Tyr His Leu Val Lys Thr Leu Tyr Met 260 265 270 Leu Gly Ser Leu Leu His Trp Pro Cys Asp Phe Asp Leu Phe Leu Met 275 280 285 Asn Ile Phe Pro Tyr Cys Thr Cys Ile Ser Tyr Val Asn Ser Cys Leu 290 295 300 Asn Pro Phe Leu Tyr Ala Phe Phe Asp Pro Arg Phe Arg Gln Ala Cys 305 310 315 320 Thr Ser Met Leu Cys Cys Gly Gln Ser Arg Cys Ala Gly Thr Ser His 325 330 335 Ser Ser Ser Gly Glu Lys Ser Ala Ser Tyr Ser Ser Gly His Ser Gln 340 345 350 Gly Pro Gly Pro Asn Met Gly Lys Gly Gly Glu Gln Met His Glu Lys 355 360 365 Ser Ile Pro Tyr Ser Gln Glu Thr Leu Val Val Asp 370 375 380 <210> 20 <211> 1140 <212> DNA <213> Unknown <220><223><400> 20 ATGGAGGAAG GTGGTGATTTT TGACAACTAC TATGGGGCAG ACAACCAGTC TGAGTGTGAG 60 TACACAGACT GGAAATCCTC GGGGGCCCTC ATCCCTGCCA TCTACATGTT GGTCTTCCTC 120 CTGGGCACCA CGGGAAACGG TCTGGTGCTC TGGACCGTGT TTCGGAGCAG CCGGGAGAAG 180 AGGCGCTCAG CTGATATCTT CATTGCTAGC CTGGCGGTGG CTGACCTGAC CTTCGTGGTG 240 ACGCTGCCCC TGTGGGCTAC CTACACGTAC CGGGACTATG ACTGGCCCTT TGGGACCTTC 300 TTCTGCAAGC TCAGCAGCTA CCTCATCTTC GTCAACATGT ACGCCAGCGT CTTCTGCCTC 360 ACCGGCCTCA GCTTCGACCG CTACCTGGCC ATCGTGAGGC CAGTGGCCAA TGCTCGGCTG 420 AGGCTGCGGG TCAGCGGGGC CGTGGCCACG GCAGTTCTTT GGGTGCTGGC CGCCCTCCTG 480 GCCATGCCTG TCATGGTGTT ACGCACCACC GGGGACTTGG AGAACACCAC TAAGGTGCAG 540 TGCTACATGG ACTACTCCAT GGTGGCCACT GTGAG CTCAG AGTGGGCCTG GGAGGTGGGC 600 CTTGGGGTCT CGTCCACCAC CGTGGGCTTT GTGGTGCCCT TCACCATCAT GCTGACCTGT 660 TACTTCTTCA TCGCCCAAAC CATCGCTGGC CACTTCCGCA AGGAACGCAT CGAGGGCCTG 720 CGGAAGCGGC GCCGGCTGCT CAGCATCATC GTGGTGCTGG TGGTGACCTT TGCCCTGTGC 780 TGGATGCCCT ACCACCTGGT GAAGACGCTG TACATGCTGG GCAGCCTGCT GCACTGGCCC 840 TGTGACTTTG ACCTCTTCCT CATGAACATC TTCCCCTACT GCACCTGCAT CAGCTACGTC 900 AACAGCTGCC TCAACCCCTT CCTCTATGCC TTTTTCGACC CCCGCTTCCG CCAGGCCTGC 960 ACCTCCATGC TCTGCTGTGG CCAGAGCAGG TGCGCAGGCA CCTCCCACAG CAGCAGTGGG 1020 GAGAAGTCAG CCAGCTACTC TTCGGGGCAC AGCCAGGGGC CCGGCCCCAA CATGGGCAAG 1080 GGTGGAGAAC AGATGCACGA GAAATCCATC CCCTACAGCC AGGAGACCCT TGTGGTTGAC 1140 <210> 21 <211> 15 <212> PRT <213g Ar Arg Arific Arific Arg Gly Pro Met Pro Phe 1 5 10 15 <210> 22 <211> 13 <212> PRT <213> Artificial Sequence <223><400> 22 Arg Arg Gln Arg Pro Arg Leu Ser Ala Arg Gly Pro Met 1 5 10 13 <210> 23 <211> 12 <212> PRT <213> Artificial Sequence <223><400> 23 Arg Arg Gln Arg Pro Arg Leu Ser Ala Arg Gly Pro 1 5 10 12 <210> 24 <211> 13 <212> PRT <213> Artificial Sequence <223> Xaa means Met (O) <400> 24 Arg Arg Gln Arg Pro Arg Leu Ser His Lys Gly Pro Xaa 1 5 10 13 <210> 25 <211> 15 <212> PRT <213> Artificial Sequence <223> Xaa means Lys (Arg-Arg) <400> 25 Arg Arg Xaa Arg Pro Arg Leu Ser His Lys Gly Pro Met Pro Phe 1 5 10 15 <210> 26 <211> 15 <212> PRT <213> Artificial Sequence <223><400> 26 Arg Arg Arg Arg Pro Arg Leu Ser His Lys Gly Pro Met Pro Phe 1 5 10 15 <210> 27 <211> 15 <212> PRT <213> Artificial Sequence <223><400> 27 Arg Arg Lys Arg Pro Arg Leu Ser His Lys Gly Pro Met Pro Phe 1 5 10 15 <210> 28 <211> 12 <212> PRT <213> Artificial Sequence <223><400> 28 Arg Pro Arg Leu Ser Ala Arg Gly Pro Met Pro Phe 1 5 10 12 <210> 29 <211> 15 <212> PRT <213> Artificial Sequence <223><400> 29 Arg Arg Ala Arg Pro Arg Leu Ser His Lys Gly Pro Met Pro Phe 1 5 10 15 <210> 30 <211> 13 <212> PRT <213> Artificial Sequence <223> Xaa means pGlu <400> 30 Xaa Arg Pro Arg Leu Ser Ala Arg Gly Pro Met Pro Phe 1 5 10 13 <210> 31 <211> 10 <212> PRT <213> Artificial Sequence <223><400> 31 Arg Pro Arg Leu Ser Ala Arg Gly Pro Met 1 5 10 <210> 32 <211> 11 <212> PRT <213> Artificial Sequence <223> Xaa means Phe (Cl) <400> 32 Arg Pro Arg Leu Ser His Lys Gly Pro Met Xaa 1 5 10 11 <210> 33 <211> 13 <212> PRT <213> Artificial Sequence <223> Xaa means pGlu <400> 33 Xaa Arg Pro Arg Leu Ser Ala Lys Gly Pro Met Pro Phe 1 5 10 13 <210> 34 <211> 13 <212> PRT <213> Artificial Sequence <223> Xaa means pGlu <400> 34 Xaa Arg Pro Arg Leu Ser Arg Lys Gly Pro Met Pro Phe 1 5 10 13 <210> 35 <211> 12 <212> PRT <213> Artificial Sequence <223><400> 35 Arg Pro Arg Leu Phe Ala Arg Gly Pro Met Pro Phe 1 5 10 12 <210> 36 <211> 12 <212> PRT <213> Artificial Sequence <223> Xaa means Nal (2) <400> 36 Arg Pro Arg Leu Ser His Lys Gly Pro Met Pro Xaa 1 5 10 12 <210> 37 <211> 15 <212> PRT <213> Artificial Sequence <223><400> 37 Arg Arg Phe Arg Pro Arg Leu Ser His Lys Gly Pro M et Pro Phe 1 5 10 15 <210> 38 <211> 13 <212> PRT <213> Artificial Sequence <223> Xaa means pGlu <400> 38 Xaa Arg Pro Arg Leu Ser His Arg Gly Pro Met Pro Phe 1 5 10 13 <210> 39 <211> 12 <212> PRT <213> Artificial Sequence <223> Xaa on the 1st position means pGlu, Xaa on the 12th position means Phe (Cl) <400> 39 Xaa Arg Pro Arg Leu Ser His Lys Gly Pro Met Xaa 1 5 10 12 <210> 40 <211> 11 <212> PRT <213> Artificial Sequence <223> Xaa means Cha <400> 40 Arg Pro Arg Leu Ser His Lys Gly Pro Met Xaa 1 5 10 11 <210> 41 <211> 11 <212> PRT <213> Artificial Sequence <223> Xaa on the 10th position means Cha, Xaa on the 11th position means Phe (Cl) <400> 41 Arg Pro Arg Leu Phe His Lys Gly Pro Xaa Xaa 1 5 10 11 <210> 42 <211> 13 <212> PRT <213> Artificial Sequence <223> Xaa means pGlu <400> 42 Xaa Arg Pro Arg Leu Ser Leu Lys Gly Pro Met Pro Phe 1 5 10 13 <210> 43 <211> 13 <212> PRT <213> Artificial Sequence <223> Xaa on the 1st position means pGlu, Xaa on the 13th position means Nal (2) <400> 43 Xaa Arg Pro Arg Leu Ser His Lys Gly Pro Met Pro Xaa 1 5 10 13 <210> 44 <211> 11 <212> PRT <213> Artificial Sequence <223> Xaa means Nal (2) <400> 44 Arg Pro Arg Leu Ser His Lys Gly Pro Met Xaa 1 5 10 11 <210> 45 <211> 13 <212> PRT <213> Artificial Sequence <223> Xaa means pGlu <400> 45 Xaa Arg Pro Arg Leu Ser Arg Arg Gly Pro Met Pro Phe 1 5 10 13 <210> 46 <211> 13 <212> PRT <213> Artificial Sequence <223> Xaa means pGlu <400> 46 Xaa Arg Pro Arg Leu Phe Arg Arg Gly Pro Met Pro Phe 1 5 10 13 <210 > 47 <211> 13 <212> PRT <213> Artificial Sequence <223> Xaa means pGlu <400> 47 Xaa Arg Pro Arg Leu Ser Phe Lys Gly Pro Met Pro Phe 1 5 10 13 <210> 48 <211> 13 <212> PRT <213> Artificial Sequence <223> Xaa means pGlu <400> 48 Xaa Arg Pro Arg Leu Phe His Lys Gly Pro Met Pro Phe 1 5 10 13 <210> 49 <211> 12 <212> PRT <213 > Artificial Sequence <223> Xaa on the 1st position means pGlu, Xaa on the 12th position means Cha <400> 49 Xaa Arg Pro Arg Leu Ser His Lys Gly Pro Met Xaa 1 5 10 12 <210> 50 <211> 12 <212> PRT <213> Artificial Sequence <223> Xaa on the 1st position means pGlu, Xaa on the 12th position means Nal (2) <400> 50 Xaa Arg Pro Arg Leu Ser His Lys Gly Pro Met Xaa 1 5 10 12 <210> 51 <211> 11 <212> PRT <213> Artificial Sequence <223><400> 51 Arg Pro Arg Leu Phe Ala Arg Gly Pro Met Phe 1 5 10 11 <210> 52 <211> 13 <212> PRT <213 > Artificial Sequence <223> Xaa means pGlu <400> 52 Xaa Arg Pro Arg Leu Ser His Phe Gly Pro Met Pro Phe 1 5 10 13 <210> 53 <211> 12 <212> PRT <213> Artificial Sequence <223> Xaa means Cha <400> 53 Arg Pro Arg Leu Ser His Lys Gly Pro Met Pro Xaa 1 5 10 12 <210> 54 <211> 13 <212> PRT <213> Artificial Sequence <223> Xaa means pGlu <400> 54 Xaa Arg Pro Arg Leu Ser His Leu Gly Pro Met Pro Phe 1 5 10 13 <210> 55 <211> 12 <212> PRT <213> Artificial Sequence <223> Xaa means NMe ₂ <400> 55 Arg Arg Gln Arg Pro Arg Leu Ser Ala Arg Gly Xaa 1 5 10 12 <210> 56 <211> 12 <212> PRT <213> Artificial Sequence <223> Xaa means Mor <400> 56 Arg Arg Gln Arg Pro Arg Leu Ser Ala Arg Gly Xaa 1 5 10 12 <210> 57 <211> 12 <212> PRT <213> Artificial Sequence <223> Xaa means Phe (Cl) <400> 57 Arg Pro Arg Leu Ser Ala Arg Gly Pro Ala Pro Xaa 1 5 10 12 <210> 58 <211> 12 <212> PRT <213> Artificial Sequence <223> Xaa means Phe (Cl) <400> 58 Arg Pro Arg Leu Ser Ala Arg Gly Gly Met Pro Xaa 1 5 10 12 <210 > 59 <211> 12 <212> PRT <213> Artificial Sequence <223> Xaa on the 9th position means N-MeAla, Xaa on the 12th position me ans Phe (Cl) <400> 59 Arg Pro Arg Leu Ser Ala Arg Gly Xaa Met Pro Xaa 1 5 10 12 <210> 60 <211> 12 <212> PRT <213> Artificial Sequence <223> Xaa on the 10th position means Cha, Xaa on the 12th position means Phe (Cl) <400> 60 Arg Pro Arg Leu Ser His Ala Gly Pro Xaa Pro Xaa 1 5 10 12 <210> 61 <211> 12 <212> PRT <213> Artificial Sequence <223> Xaa on the 10th position means Cha, Xaa on the 12th position means Phe (Cl) <400> 61 Arg Pro Arg Ala Ser His Lys Gly Pro Xaa Pro Xaa 1 5 10 12 <210> 62 <211> 12 <212> PRT <213> Artificial Sequence <223> Xaa on the 10th positi on means Cha, Xaa on the 12th position means Phe (Cl) <400> 62 Arg Pro Ala Leu Ser His Lys Gly Pro Xaa Pro Xaa 1 5 10 12 <210> 63 <211> 11 <212> PRT <213> Artificial Sequence <223> Xaa on the 10th position means Cha, Xaa on the 11th position means Pyn <400> 63 Arg Pro Arg Leu Ser Ala Arg Gly Pro Xaa Xaa 1 5 10 11 <210> 64 <211> 12 <212> PRT <213> Artificial Sequence <223> Xaa on the 10th position means Cha, Xaa on the 12th position means Pyn <400> 64 Arg Pro Arg Leu Ser Ala Arg Gly Pro Xaa Pro Xaa 1 5 10 12 <210> 65 <211> 13 <212> PRT <213> Artificial Sequence <223> Xaa on the 13th position means Cha <400> 65 Arg Arg Gln Arg Pro Arg Leu Ser Ala Arg Gly Gly Xaa 1 5 10 13 <210> 66 <211> 12 <212> PRT <213> Artificial Sequence <223> Xaa on the 3rd position means Lys (Me) ₂ <400> 66 Arg Pro Xaa Leu Ser Ala Arg Gly Pro Met Pro Phe 1 5 10 12 <210> 67 <211> 12 <212> PRT <213> Artificial Sequence <223> Xaa on the 7th position means Lys (Me) ₂ <400> 67 Arg Pro Arg Leu Ser Ala Xaa Gly Pro Met Pro Phe 1 5 10 12 <210> 68 <211> 12 <212> PRT <213> Artificial Sequence <223> Xaa on the 6th position means Dap, Xaa on the 10th position means Cha, Xaa on the 12th position means Phe (Cl) <400> 68 Arg Pro Arg Leu Ser Xaa Arg Gly Pro Xaa Pro Xaa 1 5 10 12 <210> 69 <211> 12 <212> PRT <213> Artificial Sequence <223> Xaa on the 6th position means Dap (Ac), Xaa on the 10th position me ans Cha, Xaa on the 12th position means Phe (Cl) <400> 69 Arg Pro Arg Leu Ser Xaa Arg Gly Pro Xaa Pro Xaa 1 5 10 12 <210> 70 <211> 12 <212> PRT <213> Artificial Sequence <223> Xaa on the 6th position means Dap (C ₆ ), Xaa on the 10th position me ans Cha, Xaa on the 12th position means Phe (Cl) <400> 70 Arg Pro Arg Leu Ser Xaa Arg Gly Pro Xaa Pro Xaa 1 5 10 12 <210> 71 <211> 12 <212> PRT <213> Artificial Sequence <223> Xaa on the 6th position means Dap (Adi), Xaa on the 10th position m eans Cha, Xaa on the 12th position means Phe (Cl) <400> 71 Arg Pro Arg Leu Ser Xaa Arg Gly Pro Xaa Pro Xaa 1 5 10 12

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 15/00 A61P 25/28 25/28 37/02 37/02 C07K 7/06 C07K 7/06 A61K 37 / 02 (72) Inventor Masaki Hosoya 83F term of 1-711 Itaya, Tsuchiura-shi, Ibaraki Pref. ZA892 ZA972 ZB152 ZB262 ZB332 ZC032 ZC042 ZC062 ZC242 ZC332 ZC352 ZC372 ZC392 ZC522 ZC552 4H045 AA10 AA30 BA16 BA17 BA50 EA21 EA22 EA23 EA25 EA27 EA29 FA41 GA05 GA22

Claims (22)

[Claims] 1. A compound of the formula P1-Arg-Pro-Arg-Leu-Phe-P2-P3-Gly-Pro-P4-P5 (I) wherein P1 is a hydrogen atom or the same or different side chain is substituted An amino acid residue or peptide chain consisting of 1 to 25 amino acids which may be
2 represents a neutral amino acid residue whose side chain may be substituted or a basic amino acid residue whose side chain may be substituted, and P3 represents a neutral amino acid residue whose side chain may be substituted. Represents an aromatic amino acid residue whose side chain may be substituted or a basic amino acid residue whose side chain may be substituted, and P4 represents a neutral bond or a bond whose side chain may be substituted or An aromatic amino acid residue, wherein P5 is an amino acid residue whose side chain may be substituted or an amino acid derivative having its C-terminal carboxyl group reduced to a hydroxymethyl group or formyl group, a hydroxyl group or a side chain substituted A dipeptide chain formed by combining an amino acid residue which may be substituted with an amino acid residue whose side chain may be substituted or its C-terminal carboxyl group is reduced to a hydroxymethyl group or formyl group. Shows the peptide derivative, the side chain of -Arg-Pro-Arg-Leu-Phe- or -Gly-Pro- each amino acid residue in the middle in the formula may be substituted. ] The peptide represented by these, its ester, its amide, or its salt. 2. P1 is a hydrogen atom, pGlu or Arg-
The peptide according to claim 1, which is Arg-Gln, an ester thereof, an amide thereof, or a salt thereof. 3. The peptide according to claim 1, wherein P2 is His which may be substituted or Ala which may be substituted, an ester thereof, an amide thereof or a salt thereof. 4. The peptide according to claim 1, wherein P3 is Arg which may be substituted or Lys which may be substituted, an ester thereof, an amide thereof or a salt thereof. 5. The method according to claim 1, wherein -P4-P5 is -Cha-Pro-Phe.
(Cl), -Cha-Pro-Phe, -Met-Pr
o-Phe, -Met-Pro-Phe (Cl), -C
The peptide according to claim 1, which is ha-Phe or -Met-Phe, an ester thereof, an amide thereof, or a salt thereof. 6. Arg-Pro-Arg-Leu-Phe-Ala-Arg-Gly-Pro
-Cha-Pro-Phe (Cl), Arg-Pro-Arg-Leu-Phe-His-Lys-Gly-Pro-Cha-Pro-Phe
(Cl), Arg-Pro-Arg-Leu-Phe-His-Lys-Gly-Pro-Cha-Pro-Ph
e, Arg-Pro-Arg-Leu-Phe-His-Lys-Gly-Pro-Met-Pro-Phe
(Cl), Arg-Pro-Arg-Leu-Phe-Ala-Arg-Gly-Pro-Met-Pro-Ph
e, Arg-Pro-Arg-Leu-Phe-His-Lys-Gly-Pro-Cha-Phe (C
l), pGlu-Arg-Pro-Arg-Leu-Phe-Arg-Arg-Gly-Pro-Met-Pr
o-Phe, pGlu-Arg-Pro-Arg-Leu-Phe-His-Lys-Gly-Pro-Met-Pr
The peptide according to claim 1, which is represented by o-Phe or Arg-Pro-Arg-Leu-Phe-Ala-Arg-Gly-Pro-Met-Phe, an ester thereof, an amide thereof, or a salt thereof. 7. A compound represented by the formula Q1-Arg-Pro-Arg-Leu-Ser-Ala-Q2-Gly-Q5-Q3-Q4 (II) wherein Q1 is a hydrogen atom or the same or different side chain is substituted. An amino acid residue consisting of 1 to 25 amino acids or a peptide chain,
2 represents a neutral amino acid residue whose side chain may be substituted, an aromatic amino acid residue whose side chain may be substituted or a basic amino acid residue whose side chain may be substituted,
Q3 represents a bond or a neutral or aromatic amino acid residue whose side chain may be substituted; Q4 represents an amino acid residue whose side chain may be substituted or its C-terminal carboxyl group is a hydroxymethyl group or An amino acid derivative reduced to a formyl group, a dipeptide chain in which an amino acid residue in which a hydroxyl group or a side chain may be substituted and an amino acid residue in which a side chain may be substituted or a C-terminal carboxyl group thereof is Represents a peptide derivative reduced to a hydroxymethyl group or a formyl group, Q5 represents a neutral amino acid residue whose side chain may be substituted, and -Arg-Pro-Arg-Leu-Ser-Ala in the formula
The side chain of each amino acid residue in-may be substituted. ] The peptide represented by these, its ester, its amide, or its salt. 8. Q1 is a hydrogen atom, pGlu or Arg-
The peptide according to claim 7, which is Arg-Gln, an ester thereof, an amide thereof, or a salt thereof. 9. The peptide according to claim 7, wherein Q2 is Arg which may be substituted or Lys which may be substituted, or a peptide thereof, an ester thereof, an amide thereof or a salt thereof. 10. -Q3-Q4 is -OH, -Met, -M
et-Pro-Phe, -Met-Pro-Phe (C
l), -Cha-Pro-Phe, -Cha-Pro-
Phe (Cl), -Ala-Pro-Phe (Cl),
The peptide according to claim 7, which is -Cha-Phe (Cl) or -Cha, an ester thereof, an amide thereof, or a salt thereof. 11. The peptide according to claim 7, wherein Q5 is Pro which may be substituted, Gly which may be substituted or Ala which may be substituted, or an ester thereof, an amide thereof or a salt thereof. (I) Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-
Ala-Arg-Gly-Pro-Met-Pro-Phe (Cl), (ii) Arg-Pro-Arg-
Leu-Ser-Ala-Arg-Gly-Pro-Met-Pro-Phe (Cl), (iii) Arg
-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Cha-Phe (Cl), (iv)
Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Cha-Pro-Phe (C
l), (v) Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gl
y-Pro-Cha, (vi) Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pr
o-Cha-Pro-Phe, (vii) Arg-Arg-Gln-Arg-Pro-Arg-Leu-S
er-Ala-Arg-Gly-Pro-Met-Pro-Phe, (viii) Arg-Arg-Gln
-Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Met, (ix) Arg
-Arg-Gln-Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro, (x)
Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Met-Pro-Phe,
(xi) pGlu-Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Met-
Pro-Phe, (xii) Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro
-Met, (xiii) pGlu-Arg-Pro-Arg-Leu-Ser-Ala-Lys-Gly-
Pro-Met-Pro-Phe, (xiv) Arg-Pro-Arg-Leu-Ser-Ala-Arg
-Gly-Pro-Ala-Pro-Phe (Cl), (xv) Arg-Pro-Arg-Leu-Ser
-Ala-Arg-Gly-Gly-Met-Pro-Phe (Cl), (xvi) Arg-Pro-Ar
g-Leu-Ser-Ala-Arg-Gly-NMe-Ala-Met-Pro-Phe (Cl), (xv
ii) Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Cha-Pyn,
(xviii) Arg-Pro-Arg-Leu-Ser-Ala-Arg-Gly-Pro-Cha-Pr
o-Pyn, (xix) Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-Ala-A
rg-Gly-Gly-Cha, or (xx) Arg-Pro-Arg-Leu-Ser-Ala
-Lys (Me) ₂ -Gly-Pro-Met-Pro-Phe.
Or the ester or the amide or the salt thereof. 13. A compound represented by the formula: R1-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-R2-Pro-R3 (III) wherein R1 is a hydrogen atom or is the same or different. An amino acid residue or a peptide chain consisting of 1 to 25 amino acids whose chain may be substituted,
2 represents an optionally substituted Cha, an optionally substituted Met or an optionally substituted Nle;
3 is an optionally substituted Phe (Cl), an optionally substituted Phe, an optionally substituted Nal
(2) represents optionally substituted Cha or optionally substituted Tyr, and represents -Arg-Pro-A in the formula.
rg-Leu-Ser-His-Lys-Gly-Pr
The side chain of each amino acid residue in o or -Pro- may be substituted. ] The peptide represented by these, its ester, its amide, or its salt. 14. R1 is a hydrogen atom, pGlu or Arg
The peptide according to claim 13, which is -Arg-Gln, an ester thereof, an amide thereof, or a salt thereof. 15. Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-H
is-Lys-Gly-Pro-Cha-Pro-Phe (Cl), Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Cha-Pro-Phe
(Cl), Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe
(Cl), pGlu-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Cha-Pr
o-Phe, pGlu-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pr
o-Phe (Cl), Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro
-Nle-Pro-Tyr, Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Nal
(2), pGlu-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pr
o-Nal (2), or Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Ch
14. The peptide according to claim 13, which is represented by: or an ester thereof, an amide thereof, or a salt thereof. (I) Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-
His-Lys-Gly-Pro-Met (O), (ii) Arg-Arg-Lys (Arg-Arg)-
Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe,
(iii) Arg-Arg-Arg-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-
Pro-Met-Pro-Phe, (iv) Arg-Arg-Lys-Arg-Pro-Arg-Leu-
Ser-His-Lys-Gly-Pro-Met-Pro-Phe, (v) Arg-Arg-Ala-A
rg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe, (v
i) Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Phe (C
l), (vii) pGlu-Arg-Pro-Arg-Leu-Ser-Arg-Lys-Gly-Pro
-Met-Pro-Phe, (viii) Arg-Arg-Phe-Arg-Pro-Arg-Leu-S
er-His-Lys-Gly-Pro-Met-Pro-Phe, (ix) pGlu-Arg-Pro-
Arg-Leu-Ser-His-Arg-Gly-Pro-Met-Pro-Phe, (x) pGlu-
Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Phe (Cl),
(xi) Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Cha,
(xii) pGlu-Arg-Pro-Arg-Leu-Ser-Leu-Lys-Gly-Pro-Met
-Pro-Phe, (xiii) Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-P
ro-Met-Nal (2), (xiv) pGlu-Arg-Pro-Arg-Leu-Ser-Arg-
Arg-Gly-Pro-Met-Pro-Phe, (xv) pGlu-Arg-Pro-Arg-Leu
-Ser-Phe-Lys-Gly-Pro-Met-Pro-Phe, (xvi) pGlu-Arg-P
ro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Cha, (xvii) pGl
u-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Nal (2),
(xviii) pGlu-Arg-Pro-Arg-Leu-Ser-His-Phe-Gly-Pro-M
et-Pro-Phe, (xix) pGlu-Arg-Pro-Arg-Leu-Ser-His-Leu
-Gly-Pro-Met-Pro-Phe, (xx) Arg-Arg-Gln-Arg-Pro-Arg
-Leu-Ser-Ala-Arg-Gly-NMe2, (xxi) Arg-Arg-Gln-Arg-P
ro-Arg-Leu-Ser-Ala-Arg-Gly-Mor, (xxii) Arg-Pro-Arg
-Leu-Ser-His-Ala-Gly-Pro-Cha-Pro-Phe (Cl), (xxiii)
Arg-Pro-Arg-Ala-Ser-His-Lys-Gly-Pro-Cha-Pro-Phe (C
l), (xxiv) Arg-Pro-Lys (Me) ₂ -Leu-Ser-Ala-Arg-Gly-Pr
o-Met-Pro-Phe, (xxv) Arg-Pro-Arg-Leu-Ser-Dap-Arg-G
ly-Pro-Cha-Pro-Phe (Cl), (xxvi) Arg-Pro-Arg-Leu-Ser
-Dap (Ac) c-Arg-Gly-Pro-Cha-Pro-Phe (Cl), (xxvii) Arg
-Pro-Arg-Leu-Ser-Dap (C6) -Arg-Gly-Pro-Cha-Pro-Phe (C
l), (xxviii) Arg-Pro-Arg-Leu-Ser-Dap (Adi) -Arg-Gly-
Pro-Cha-Pro-Phe (Cl) or (xxix) Arg-Pro-Ala-Leu-
A peptide represented by Ser-His-Lys-Gly-Pro-Cha-Pro-Phe (Cl), its ester, its amide, or its salt. 17. A pharmaceutical comprising the peptide according to claim 1, 7, 13, or 16 or an ester thereof, an amide thereof or a salt thereof. 18. A central nervous function regulator, a circulatory function regulator,
Heart function regulator, immune function regulator, digestive function regulator,
2. A metabolic function regulator or a genital function regulator.
7. The medicament according to 7. 19. The medicament according to claim 17, which is a prophylactic / therapeutic agent for HIV infection or AIDS. 20. An agent of a protein having an amino acid sequence represented by SEQ ID NO: 19 or a salt thereof.
7. The medicament according to 7. 21. A method for producing a medicament comprising the peptide according to claim 1, 7, 7, 13 or 16, or an ester or amide thereof, or a salt thereof. Use of the peptide according to claim 13 or 16 or an ester or amide thereof or a salt thereof. 22. Prevention of HIV infection or AIDS, comprising administering the peptide of claim 1, claim 7, claim 13, or claim 16 or an ester or amide or salt thereof to a mammal. ·Method of treatment.